Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor (PPAR) α

ABSTRACT

The invention provides novel substituted phenylpropanoic acid derivatives that activate by binding to receptor as ligands of human peroxisome preliferant-activated receptor α (PPARα), and exhibit potent decreasing action on lipids in blood (cholesterol and triglyceride). 
     It relates to a substituted phenylpropanoic acid derivatives represented by a general formula (1),                    
     their pharmaceutically acceptable salts and their hydrates, and processes for preparing them.

TECHNICAL FIELD

The present invention relates to substituted phenylpropanoic acidderivatives, effective for the therapy of abnormality of lipidmetabolismas agonists of human peroxisome proliferant-activated receptor(abbreviated as PPAR), in particular, as agonists for human PPARαisoform, their addition salts and their hydrates, processes forpreparing them, and medicinal compositions containing these compounds.

BACKGROUND TECHNOLOGIES

The peroxisome proliferant-activated receptor (PPAR)'s are aligand-dependent transcription factors that belong to nuclear receptorsuperfamily, such as steroid receptor, retinoid receptor, thyroidreceptor, etc. Three isoforms (α type, β (or δ) type and γ type) withdifferent histological distribution have been identified hitherto inhuman and various animal species (Proc. Natl. Acad. Sci., 1992, 89,4653). Thereamong, the PPARα is distributed in the liver, kidney, etc.,with high catabolic capacity for fatty acids and, in particular highexpression is recognized in the liver, (Endo-crinology, 1995, 137, 354),positively or negatively controlling the expressions of genes relevantto the metabolism and the intracellular transport of fatty acids (e.g.acyl CoA synthetic enzyme, fatty acid-binding protein and lipoproteinlipase) and apolipoprotein (AI, AII, CIII) genes relevant to themetabolisms of cholesterol and neutral lipid. The PPARβ is expressedubiquitously in the tissues or organisms, including nerve cells. Atpresent, the physiological significance of PPARβ is unclear. The PPARγis highly expressed in the adipocytes and involved the differentiationof adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoformof PPAR play specific function in the particular organs and tissues.

Moreover, it is reported that a knock-out mouse of PPARα exhibitshypertriglyceridemia with ageing and becomes obesity mainly byincreasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577),hence the relevance between activation of PPARα and decreasing action oflipids (cholesterol and triglyceride) in blood is suggested strongly.

On the other hand, fibrates and statins are widely used so far as thetherapeutic drugs for hyperlipidemia. However, the fibrates have onlyweak decreasing effect of cholesterol, while the statins have weakdecreasing effect of free fatty acids and triglycerides. Moreover, withrespect to the fibrates, various adverse effects such asgastrointestinal injury, anthema, headache, hepatic disorder, renaldisorder and biliary calculus are reported. The reason is considered tobe due to that the fibrates exhibit extensive pharmacological function,hence the development of a therapeutic drug for hyperlipidemia withspecific mechanism is desired.

When considering the present situation of such conventional therapeuticdrugs for hyperlipidemia, and the role on the adjusting mechanism oflipidmetabolism and the connection to the pathology of hyperlipidemia oftranscription factor called PPARα, which has become clear until now, ifa compound that binds directly to as a ligand of PPARα, in particular,human PPARα and is capable of activating human PPARα could be created,the medicinal use thereof would be expected as a compound that exhibitsthe decreasing effect of lipids (both of cholesterol and triglyceride)in blood due to very specific mechanism.

Prior arts

For compounds having an affinity to PPARα as ligands of PPARα,eicosanoids in HETE (hydroxyeicosatetraenoic acid) group produced viaoxidation with cytochrome P-450, in particular, 8-HETE, 8-HEPE, etc. arereported in addition to LTB₄ being a metabolite of arachidonic acid(Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenousunsaturated fatty acid derivatives are unstable metabolically andchemically and cannot be offered as medicinal drugs.

On the other hand, as compounds with similar structure to the inventivesubstituted phenylpropanoic acid derivatives, a group of compounds shownbelow, etc. are reported.

As compounds with glucose-lowering action, in International PublicationNumber WO98/28254 (Nippon Chemiphar Co., Ltd.), compounds represented bya general formula (A)

(wherein A¹ denotes aryl group which may have substituent orhetero-cycle group, Y² denotes alkylene chain with carbon atoms of 1 to5, X⁴ denotes bond hand, oxygen atom or sulfur atom, W¹ denotesnaphthalene ring which may have substituent, quinoline ring, indolering, benzisoxazole ring or benzo[b]thiophene ring, R⁴ denotes hydrogenatom or alkyl group with carbon atoms of 1 to 8, X⁵ denotes oxygen atomor sulfur atom, and R⁵ denotes alkyl group with carbon atoms of 1 to 8which may have substituent, aralkyl group or aryl group), are reported.These compounds however have different structure from that of theinventive compounds in that carbonyl group or amide group is notcontained in Y² and X⁴ being connecting portions and that W¹ to bind to3-position of propanoic acid is heterocycle, and it is also notdescribed that these compounds have the binding activity to human PPARαand the transcription-activating function.

As propanoic acid derivatives with glucose-lowering action andlipid-decreasing effect, in International Publication Number WO98/07699(Japan Tobacco Inc.), compounds represented by a general formula (B)

(wherein R denotes a substituent represented by D₁ or D₂, R¹ denotesaromatic ring, cycloalkyl group or heteroaromatic ring, R⁵ denotes alkylgroup, R⁴ denotes hydrogen atom or alkyl group, R⁶ denotes hydrogen atomor it may be connected to R⁹ to form double bond, R⁷ denotes carboxylgroup, acyl group, alkoxycarbonyl group which may have substituent,alkyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoylgroup, NHR⁸ group or OR⁸ group, R⁸ denotes acyl group which may havesubstituent or alkoxycarbonyl group, R⁹ denotes hydrogen atom, alkylgroup or alkoxycarbonyl group, and R¹⁰ denotes hydrogen atom, aminogroup, alkoxy group, alkyl group, aryloxy group or aralkyloxy group),are reported. However, these compounds also have different structurefrom that of the inventive compounds in that substituents on benzenering are of disubstituted form at 1-position and 4-position, and it isalso not described that these compounds have the binding activity tohuman PPARα and the transcription-activating function.

As carboxylic acid derivatives with agonistic effect on leukotrienereceptor, in Jpn. Kokai Tokkyo Koho JP 63-91354 (YamanouchiPharmaceutical Co., Ltd.), compounds represented by a general formula(C)

(wherein A denotes hydrogen atom or phenyl group, m denotes integer of 3to 10, n denotes integer of 1 to 6, X denotes CONH group or NHCO group,and R denotes carboxy lower alkyl group or carboxy lower alkylcarbamoylgroup (however, when A is phenyl group, R is carboxy loweralkylcarbamoyl lower alkyl group)), are reported. Among these compounds,however, propanoic acid derivatives have no substituent at 2-positionand carbonyl groups exist in all of R group portions, hence thestructure differs from that of the inventive compounds, and it is alsonot described that these compounds have the binding activity to humanPPARα and the transcription-activating function.

As carboxylic acid derivatives with antagonism against fibrinogenreceptor, in U.S. Pat. No. 5,227,490 (Merck & Co.,Inc.), compoundsrepresented by a general formula (D)

(wherein R¹ denotes hydrogen atom, C₁₋₆ alkyl group, aryl C₄₋₁₀ alkylgroup, aryl group, carboxyl group, C₁₋₆ alkoxy group, carboxy C₀₋₆ alkylgroup, carboxy C₀₋₆ alkoxy group, hydroxy C₁₋₆ alkyl group, C₁₋₄alkylsulfonyl C₀₋₆ alkyl group, C₀₋₄ alkylamino C₀₋₆ alkyl group, arylC₀₋₁₀ alkylamino C₀₋₆ alkyl group, C₂₋₁₀ acylamino C₀₋₆ alkyl group,C₁₋₄ carboalkoxy C₀₋₆ alkyl group or halogen atom, R²s denoteidentically or differently hydrogen atoms, halogen atoms, hydroxylgroups, C₁₋₆ alkoxy groups, aryl C₀₋₄ alkyl groups, aryl C₀₋₆ alkoxygroups or C₁₋₆ alkyl groups which may have substituent, R³ denoteshydrogen atom, C₁₋₆ alkyl group or aryl C₁₋₁₀ alkyl group, X denotesoxygen atom, sulfur atom, SO group, SO₂ group, CO group, NR⁴CO group,CONR⁴ group, CH₂ group, CH═CH group or NR⁴CS group, Y denotes C₁₋₁₀alkyl group which is unsubstituted or which may have substituent, C₄₋₈cycloalkyl group, aryl group, C₀₋₃ alkyl-aryl C₀₋₃ alkyl group, C₀₋₃alkylaryl C₀₋₃ alkylcarbonyl group, C₀₋₃ alkylaryl C₀₋₃alkylcarboxyamide group, C₀₋₃ alkylaryloxy C₀₋₃ alkyl group, CONH group,NHCO group or (CH₂)m-Q-(CH₂)n (however, Q denotes C₃₋₈ memberedheterocycle containing 1 to 3 kinds of heteroatoms selected from oxygenand sulfur, and m and n denote 0 to 4), and Z denotes NR⁴R⁵ group(however, R⁴ and R⁵ denote identically or differently hydrogen atoms,C₁₋₆ alkyl groups, aryl C₁₋₁₀ alkyl groups in which alkyl group isunsubstituted or may be substituted with C₁₋₄ alkoxy group, carboxy C₀₋₆alkyl group, hydroxyl group, halogen atom, or 4-9 membered monocyclic orbicyclic ring containing 1 to 3 heteroatoms selected from nitrogen,oxygen and sulfur) or guanidino group which may have substituent), arereported. However, from the fact that these compounds are amino acidderivatives inevitably containing amino group which may havesubstituents in all of Z group portions, the structure is different fromthat of the inventive compounds, and it is also not described that thesecompounds have the binding activity to human PPARα and thetranscription-activating function.

With respect to patents that report the agonistic effect on PPARα,compounds represented by a general formula (E)

(wherein R^(a) denotes 2-benzoxazolyl group or 2-pyridyl group, andR^(b) denotes methoxymethyl group or trifluoromethyl group), arereported in International Publication Number WO97/25042 (SmithKlineBeecham plc.) as compounds with working functions on PPARα and PPARγ.However, the structure of these compounds is different from that of theinventive compounds in that substituents on benzene ring are ofdisubstituted derivatives at 1-position and 2-position, and further itis not described that they have the binding activity to human PPARα andthe transcription-activating function.

As compounds with agonistic effect on PPARα, in InternationalPublication Number WO97/36579 (Glaxo Welcome Corp.), compoundsrepresented by a general formula (F)

(wherein X denotes hydrogen atom or fluorine atom), are reported.However, the structure is different from that of the inventive compoundsin that these compounds are phenoxyacetic acid derivatives and theposition relationship of substituents on benzene ring is ofdisubstituted form at 1-position and 4-position. Also, thetranscription-activating function of PPARα is never satisfied instrength.

SUBJECTS TO BE SOLVED BY THE INVENTION

The hyperlipidemia is a risk factor of arteriosclerosis and, from aviewpoint of the prevention of arteriosclerotic diseases, in particular,coronary arteriosclerosis, the development of a therapeutic drug forhyperlipidemia with effectiveness and high safety is desired clinically.

DISCLOSURES OF THE INVENTION

As a result of diligent studies paying an attention to such specificrole on the lipidmetabolism of human PPARα, aiming at the creation ofstructurally novel drug with effectiveness and high safety as atherapeutic drug for hyperlipidemia, the inventors have found that novelsubstituted phenylpropanoic acid derivatives represented by a followinggeneral formula (1) have excellent binding activity to human PPARα andtranscription-activating function and exhibit the lipid-decreasingeffect, leading to the completion of the invention. Namely, theinvention relates to substituted phenylpropanoic acid derivativesrepresented by a general formula (1)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R² denotes a lower alkyl group with carbon atoms of 1 to4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3,phenylthio group or benzylthio group, R³ de-notes a hydrogen atom orlower alkyl group with carbon atoms of 1 to 4 in the case of R² beinglower alkyl group with carbon atoms of 1 to 4 or 2,2,2-trifluoroethylgroup, and it denotes a hydrogen atom in the case of R² being loweralkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthiogroup with carbon atoms of 1 to 3, phenylthio group or benzylthio group,and R⁴ denotes a lower alkoxy group with carbon atoms of 1 to 3], theirpharmaceutically acceptable salts and their hydrates.

The salts of the compounds represented by the general formula (1) in theinvention are of common use and metal salts, for example, alkali metalsalts (e.g. sodium salt, potassium salt, lithium salt, etc.), alkalineearth metal salts (e.g. calcium salt, magnesium salt, etc.), aluminumsalt, and other pharmaceutically acceptable salts are mentioned.

Moreover, the compounds represented by the general formula (1) in theinvention sometimes include optical isomers based on the propanoic acidportion. Such isomers and their mixtures are all included in the scopeof the invention.

The enantiomers can be prepared through stereoselective syntheticprocess. Moreover, they can also be prepared by separatingdiastereomeric ester derivatives or oxazolidinone derivatives obtainableby reacting with optically active alcohol derivatives or opticallyactive oxazolidinone derivatives by a technique of fractionalcrystallization or chromatography, followed by hydrolysis. Furthermore,they can also be prepared by a technique of chromatography that useschiral support.

In the general formula (1) of the invention, for “lower alkyl group withcarbon atoms of 1 to 4”, straight chain or branched ones with carbonatoms of 1 to 4 such as methyl, ethyl, propyl, isopropyl and butyl arementioned.

For “lower alkoxy group with carbon atoms of 1 to 3”, straight chain orbranched ones with carbon atoms of 1 to 3 such as methoxy, ethoxy,isopropoxy and propoxy are mentioned.

For “halogen atoms”, fluorine atom, chlorine atom, bromine atom andiodine atom are mentioned.

For “lower alkylthio group with carbon atoms of 1 to 3”, straight chainor branched ones with carbon atoms of 1 to 3 such as methylthio,ethylthio and propylthio are mentioned.

For substituents acceptable in “phenyl group which is unsubstituted ormay have substituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents”, lower alkyl group with carbon atoms of 1 to 4, loweralkoxy group with carbon atoms of 1 to 3, halogen atom ortrifluoromethyl group are mentioned.

The compounds of the invention can be prepared, for example, throughfollowing processes (Scheme 1).

Namely, compounds represented by a general formula (1b)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R^(2′) denotes a lower alkyl group with carbon atoms of 1to 4, lower alkoxy group with carbon atoms of 1 to 3 or phenoxy group,and R⁴ denotes a lower alkoxy group with carbon atoms of 1 to 3], can beprepared by reacting (Wittig reaction or Horner-Emmons reaction; firstprocess) compounds represented by a general formula (2)

[wherein R⁴ is as described above], and by a general formula (6)

[wherein R^(2′) is as described above, R⁵ is a lower alkyl group withcarbon atoms of 1 to 4, and X denotes PPh₃ group or PO(OC₂H₅)₂ group],in the presence of base, to synthesize compounds represented by ageneral formula (3)

[wherein R^(2′), R⁴ and R⁵ are as described above], by reducing andhydrogenolysis (second process) of these compounds, to obtain compoundsrepresented by a general formula (4)

[wherein R^(2′), R⁴ and R⁵ are as described above], by reacting (thirdprocess) these compounds with compounds represented by a general formula(7)

[wherein R¹ is as described above], to obtain compounds represented by ageneral formula (5)

[wherein R¹, R^(2′), R⁴ and R⁵ are as described above], and byhydrolizing (fourth process) COOR⁵ position of these compounds.

In the Wittig reaction or Horner-Emmons reaction of the first process,as the base, for example, alkali metal hydride such as sodium hydride,organometallic compound such as butyl lithium, metal amide such aslithium diisopropylamide, or metal alkoxides such as sodium methoxide orpotassium t-butoxide can be used in a solvent such as tetrahydrofuran,toluene, dioxane or N,N-dimethylformamide. The reaction can be performedat a reaction temperature of −20° C. to 150° C., preferably 0° C. to 50°C.

The reduction being the second process can be performed at a hydrogenpressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol,tetrahydrofuran, ethyl acetate or N,N-dimethyl-formamide in the presenceof metallic catalyst such as palladium on activated carbon, platinum onactivated carbon, platinum oxide or rhodium on alumina. The reaction canbe performed at a reaction temperature of 0° C. to 100° C., preferablyroom temperature to 80° C.

The condensation of the third process can be performed by leavingcarboxyl group as it is or converting it to reactive derivatives.

As the “reactive derivative groups of carboxyl group”, acid chloride,acid bromide, acid anhydride, carbonylimidazole or the like ismentioned. In the case of the reaction using reactive derivatives, thereaction can be performed in a solvent such as dioxane orN,N-dimethylformamide in the presence or absence of, for example, alkalimetal hydride such as sodium hydride, alkali metal hydroxide such assodium hydroxide, alkali metal carbonate such as potassium carbonate, ororganic base such as pyridine or triethylamine as a base.

In the case of the condensation by using leaving carboxylic acid form asit is, the reaction can be performed in a solvent such as methylenechloride, chloroform, dioxane or N,N-dimethylformamide in the presenceof condensing agent in the presence or absence of base, and further inthe presence or absence of additive.

As the condensing agent, for example, dicyclohexylcarbodiimide,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethylcyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or thelike can be mentioned. As the base, for example, alkali metal hydroxidesuch as sodium hydroxide, alkali metal carbonate such as potassiumcarbonate, or organic base such as pyridine or triethylamine can bementioned. As the additive, N-hydroxybenzotriazole,N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine orthe like can be mentioned. The reaction can be performed at a reactiontemperature of −20° C. to 100° C., preferably 0° C. to 50° C.

The hydrolysis of the fourth process can be performed under alkalinecondition. For the alkaline condition, lithium hydroxide, sodiumhydroxide, potassium hydroxide or the like is used. The reaction can beperformed at a reaction temperature of 0° C. to 80° C., preferably roomtemperature to 60° C.

Moreover, compounds represented by the general formula (1b) can also besynthesized through following processes (Scheme 2).

Namely, compounds represented by the general formula (1b) [wherein R¹,R^(2′) and R⁴ are as described above], can be prepared by reacting(Wittig reaction or Horner-Emmons reaction; fifth process) compoundsrepresented by a general formula (8)

[wherein R¹ and R⁴ are as described above], with compounds representedby the general formula (6)

[wherein R^(2′), R⁵ and X are as described above], in the presence ofbase, to synthesize compounds represented by a general formula (9)

[wherein R¹, R^(2′), R⁴ and R⁵ are as described above], by reducing(sixth process) these compounds, to obtain compounds represented by thegeneral formula (5)

[wherein R¹, R^(2′), R⁴ and R⁵ are as described above], and byhydrolyzing (seventh process) COOR⁵ position of these compounds.

The reaction of the fifth process can be performed through the processsimilar to the reaction of the first process. The reaction of the sixthprocess can be performed through the process similar to the reaction ofthe second process. The reaction of the seventh process can be performedthrough the process similar to the reaction of the fourth process.

Compounds represented by a general formula (1c) can be synthesizedthrough following processes (Scheme 3).

Namely, compounds represented by the general formula (1c)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R^(2″) denotes a lower alkylthio group with carbon atomsof 1 to 3, phenylthio group or benzylthio group, and R⁴ denotes a loweralkoxy group with carbon atoms of 1 to 3], can be prepared by reducing(reduction reaction) nitro group of compounds represented by a generalformula (10)

[wherein R¹ and R⁴ are as described above], and then conducting Meerweinarylation reaction (eighth process), to obtain compounds represented bya general formula (11)

[wherein R¹ and R⁴ are as described above, R⁵ is a lower alkyl groupwith carbon atoms of 1 to 4, and Y denotes a halogen atom], by reacting(ninth process) these compounds with compounds represented by a generalformula (13)

[wherein R^(2″) is as described above], in the presence of base, toobtain compounds represented by a general formula (12)

[wherein R¹, R^(2″), R⁴ and R⁵ are as described above], and byhydrolyzing (tenth process) COOR⁵ portion [R⁵ is as described above] ofthese compounds.

The reaction of the eighth process can be performed first at a hydrogenpressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol,tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presenceof metallic catalyst such as palladium on activated carbon, platinum onactivated carbon, platinum oxide or rhodium on alumina. The reaction canbe performed at a reaction temperature of 0° C. to 100° C., preferablyroom temperature to 80° C. Next Meerwein arylation reaction can beperformed by reacting sodium nitrite in aqueous solution of hydrogenhalide such as hydrochloric acid or hydrobromic acid to synthesizediazonium salt, and then by adding acrylic ester such as methyl acrylateor ethyl acrylate and cuprous salt such as copper oxide (I). Thesynthesis of diazonium salt can be performed at a reaction temperatureof −40° C. to 0° C., preferably −20° C. to −5° C. Next reaction withacrylic ester can be performed at 0° C. to 50° C., preferably roomtemperature to 40° C.

The reaction of the ninth process can be performed in a solvent such asethanol, methanol or N,N-dimethylformamide, using, for example, alkalimetal hydride such as sodium hydride, alkali metal hydroxide such assodium hydroxide, alkali metal carbonate such as potassium carbonate, orthe like as a base. The reaction can be performed at a reactiontemperature of room temperature to 180° C., preferably at refluxtemperature of the solvent.

The reaction of the tenth process can be performed through the processsimilar to the reaction of the fourth process.

Compounds represented by a general formula (1d) can be synthesizedthrough following processes (Scheme 4).

Namely, compounds represented by the general formula (1d)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R^(2′″) denotes a lower alkyl group with carbon atoms of 1to 4 or 2,2,2-trifluoroethyl group, R³ denotes a hydrogen atom or loweralkyl group with carbon atoms of 1 to 4, and R⁴ denotes a lower alkoxygroup with carbon atoms of 1 to 3], can be prepared by reacting(Tetrahedron Letters, 1997, 38, 2645; eleventh process) compoundsrepresented by a general formula (14)

[wherein R⁴ is as described above], with compounds represented by ageneral formula (22)

[wherein R^(2′″) and R³ are as described above, R⁵ is a lower alkylgroup with carbon atoms of 1 to 4, and Z denotes a trimethylsilyl groupor t-butyldimethylsilyl group], in the presence of a catalytic amount ofLewis acid, to synthesize compounds represented by a general formula(15)

[wherein R^(2′″), R³, R⁴ and R⁵ are as described above], byhydrogenolysis (twelfth process) these compounds, to obtain compoundsrepresented by a general formula (16)

[wherein R^(2′″), R³, R⁴ and R⁵ are as described above], by reacting(thirteenth process) these compounds with compounds represented by thegeneral formula (7)

[wherein R¹ is as described above], to obtain compounds represented by ageneral formula (17)

[wherein R^(2′″), R³, R⁴ and R⁵ are as described above], and byhydrolyzing (fourteenth process) COOR⁵ position of these compounds.

The reaction of the eleventh process can be performed in a solvent suchas dichloromethane, tetrahydrofuran, toluene or dioxane, using, forexample, magnesium perchlorate, magnesiumbistrifluoromethanesulfonylimide, titanium tetrachloride or the like asa Lewis acid. The reaction can be performed at a reaction temperature of−20° C. to 80° C., preferably 0° C. to 50° C.

The reaction of the twelfth process can be performed through the processsimilar to the reaction of the second process. The reaction of thethirteenth process can be performed through the process similar to thereaction of the third process. The reaction of the fourteenth processcan be performed through the process similar to the reaction of thefourth process.

Moreover, optically active compounds of the general formula (1a) can beprepared, for example, through following processes (Scheme 5).

Namely, optically active substituted phenylpropanoic acid derivativesrepresented by the general formula (1a)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R² denotes a lower alkyl group with carbon atoms of 1 to4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3,phenylthio group or benzylthio group, and R⁴ denotes a lower alkoxygroup with carbon atoms of 1 to 3], can be prepared by reacting(fifteenth process) compounds represented by the general formula (2)

[wherein R⁴ is as described above], with compounds represented by ageneral formula (18)

[wherein R² is as described above, and Xp denotes a chiral oxazolidinonederivative with absolute configuration being (S) such as(S)-4-benzyl-2-oxazolidinone-3-yl group,(S)-4-isopropyl-2-oxazolidi-none-3-yl group or(S)-4-phenyl-2-oxazolidinone-3-yl group, or the like], in the presenceof metal ligand and base, to synthesize compounds represented by ageneral formula (19)

[wherein R², R⁴ and Xp are as described above], by eliminating hydroxylgroup of these compounds and hydrogenolysis (sixteenth process), toobtain compounds represented by a general formula (20)

[wherein R², R⁴ and Xp are as described above], by reacting (seventeenthprocess) these compounds with compounds represented by the generalformula (7)

[wherein R¹ is as described above], to obtain compounds represented by ageneral formula (21)

[wherein R¹, R², R⁴ and Xp are as described above], and by hydrolyzing(eighteenth process) COXp position of these compounds.

The reaction of the fifteenth process can be performed in a solvent suchas tetrahydrofuran, methylene chloride or diethyl ether, usingdi-n-butylboryltrifurate, diethylboryltrifurate, titanium tetrachlorideor the like as a metal ligand and tertiary amine such as triethylamine,diisopropylethylamine or ethyldimethylamine as a base. The reaction canbe performed at a reaction temperature of −100° C. to room temperature,preferably −80° C. to 0° C.

The reaction of the sixteenth process can be performed in a solvent suchas acetic acid or trifluoroacetic acid in the presence of triethylsilaneor trichlorosilane. The reaction can be performed at a reactiontemperature of −20° C. to 50° C., preferably 0° C. to room temperature.

The reaction of the seventeenth process can be performed through theprocess similar to the reaction of the third process.

The reaction of the eighteenth process can be performed under alkalinecondition. For alkaline condition, lithium hydroxide, sodium hydroxide,mixture of lithium hydroxide with hydrogen peroxide, or the like isused. The reaction can be performed at a reaction temperature of −20° C.to 100° C., preferably 0° C. to 50° C.

Moreover, optically active compounds being said general formula (1a) canbe prepared, for example, through following processes (Scheme 6).

Namely, optically active substituted phenylpropanoic acid derivativesrepresented by the general formula (1a)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R² denotes a lower alkyl group with carbon atoms of 1 to4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3,phenylthio group or benzylthio group, and R⁴ denotes a lower alkoxygroup with carbon atoms of 1 to 3], can be prepared by reactingcompounds represented by the general formula (1e)

[wherein R¹, R² and R⁴ are as described above], with pivaloyl chloridein the presence of base, to obtain compounds represented by a generalformula (23)

[wherein R¹, R² and R⁴ are as described above], by reacting (nineteenthprocess) these compounds with compounds represented by a general formula(24)

[wherein Xp′ denotes an optically active chiral oxazolidinone derivativesuch as optically active 4-benzyl-2-oxazolidinone-3-yl group,4-isopropyl-2-oxazolidinone-3-yl group or 4-phenyl-2-oxazolidinone-3-ylgroup, amide derivative, sultam derivative or the like], in the presenceof base, to synthesize compounds represented by a general formula (25)

[wherein R¹, R², R⁴ and Xp′ are as described above], by separating eachdiastereomer of these compounds by fractional recrystallization orcolumn chromatography, to obtain compounds represented by a generalformula (26)

[wherein R¹, R², R⁴ and Xp′ are as described above], and by hydrolyzing(twentieth process) Xp′ portion of these compounds.

In the reaction of the nineteenth process, first, the synthesis ofcompounds represented by the general formula (23)

[wherein R¹, R² and R⁴ are as described above], can be performes in asolvent such as tetrahydrofuran, methylene chloride or diethyl ether,using tertiary amine such as triethylamine, diisopropylethylamine,ethyldimethylamine or pyridine as a base. The reaction can be performedat a reaction temperature of −100° C. to room temperature, preferably−40° C. to 0° C.

Next, the reaction between general formula (23)

[wherein R¹, R² and R⁴ are as described above], and the general formula(24)

[wherein Xp′ is as described above], can be performed in a solvent suchas tetrahydrofuran, methylene chloride or diethyl ether, in the presenceof a base of alkali metal hydride such as sodium hydride, organometalliccompound such as butyl lithium, metal amide such as lithiumdiisopropylamide, or metal alkoxide such as sodium methoxide orpotassium t-butoxide, or the like. The reaction can be performed at areaction temperature of −100° C. to room temperature, preferably −40° C.to 0° C.

The reaction of the twentieth process can be performed under alkalinecondition. For alkaline condition, lithium hydroxide, sodium hydroxide,mixture of lithium hydroxide with hydrogen peroxide, or the like isused. The reaction can be performed at a reaction temperature of −20° C.to 100° C., preferably 0° C. to 50° C.

Moreover, optically active compounds being said general formula (1a) canalso be prepared, for example, through following processes (Scheme 7).

Namely, optically active substituted phenylpropanoic acid derivativesrepresented by the general formula (1a)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4,lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group,trifluoromethoxy group, phenyl group which is unsubstituted or may havesubstituents, phenoxy group which is unsubstituted or may havesubstituents or benzyloxy group which is unsubstituted or may havesubstituents, R² denotes a lower alkyl group with carbon atoms of 1 to4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3,phenylthio group or benzylthio group, and R⁴ denotes a lower alkoxygroup with carbon atoms of 1 to 3], can be prepared by reacting(twenty-first process) compounds represented by a general formula (27)

[wherein R⁴ is as described above], with compounds represented by ageneral formula (30)

[wherein R² is as described above, and Xp″ denotes a chiraloxazolidinone with absolute configuration being (R) such as(R)-4-benzyl-2-oxazolidinone-3-yl group,(R)-4-isopropyl-2-oxazolidinone-3-yl-group or(R)-4-phenyl-2-oxazolidinone-3-yl group, chiral imidazolidinone, chiralcyclic lactam, chiral sultam or the like], in the presence of base, toafford compounds represented by a general formula (28)

[wherein R², R⁴ and Xp″ are as described above], which washydrogenolysed (twenty-second process) in the presence of base to obtaincompounds represented by a general formula (29)

[wherein R², R⁴ and Xp″ are as described above], by reacting(twenty-third process) these compounds with compounds represented by thegeneral formula (7)

[wherein R¹ is as described above], to obtain compounds represented by ageneral formula (26a)

[wherein R¹, R², R⁴ and Xp″ are as described above], and by hydrolyzing(twenty-fourth process) COXp″ position of these compounds.

For the reaction of the twenty-first process, for example, alkali metalhydride such as sodium hydride, organometallic compound such as butyllithium, metal amide such as lithium diisopropylamide or sodiumbis(trimethylsilyl)amide can be used as a base in a solvent such astetrahydrofuran, diethyl ether or hexane. The reaction can be performedat a reaction temperature of −100° C. to room temperature, preferably−80° C. to 0° C.

The reaction of the twenty-second process can be performed at a hydrogenpressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol,tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presenceof metallic catalyst such as palladium on activated carbon, platinum onactivated carbon, platinumoxide or rhodium on alumina. The reaction canbe performed at a reaction temperature of 0° C. to 100° C., preferablyroom temperature to 80° C.

The reaction of the twenty-third process can be performed by leavingcarboxyl group as it is or converting it to reactive derivatives. As the“reactive derivative group of carboxyl group”, acid chloride, acidbromide, acid anhydride, carbonylimidazole or the like is mentioned.

In the case of the reaction using reactive derivative, the reaction canbe performed in a solvent such as dioxane or N,N-dimethylformamide inthe presence or absence of, for example, alkali metal hydride such assodium hydride, alkali metal hydroxide such as sodium hydroxide, alkalimetal carbonate such as potassium carbonate, or organic base such aspyridine or triethylamine as a base.

In the case of conducting the reaction by leaving carboxylic acid formas it is, the reaction can be performed in a solvent such as methylenechloride, chloroform, dioxane or N,N-dimethylformamide in the presenceof condensing agent in the presence or absence of base, and further inthe presence or absence of additive.

As the condensing agent, for example, dicyclohexylcarbodiimide,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethylcyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or thelike can be mentioned. As the base, for example, alkali metal hydroxidesuch as sodium hydroxide, alkali metal carbonate such as potassiumcarbonate, or organic base such as pyridine or triethylamine can bementioned. As the additive, N-hydroxybenzotriazole,N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine orthe like can be mentioned. The reaction can be performed at a reactiontemperature of −20° C. to 100° C., preferably 0° C. to 50° C.

The reaction of the twenty-fourth process can be performed underalkaline condition. For alkaline condition, lithium hydroxide, sodiumhydroxide, mixture of lithium hydroxide with hydrogen peroxide, or thelike is used. The reaction can be performed at a reaction temperature of−20° C. to 100° C., preferably 0° C. to 50° C.

As the administrating form of the inventive novel compounds, forexample, oral administration with tablet, capsule, granule, powder,inhalant, syrup or the like, or parenteral administration withinjection, suppository or the like can be mentioned.

Best embodiment to put the invention into practice

EXAMPLE 1 Ethyl 3-(3-carboxy-4-methoxyphenyl)-2-ethylpropanate

Sodium hydride (214 mg, 5.35 mmol) was suspended in 10 ml of dehydratedtetrahydrofuran under an atmosphere of argon, which was cooled with ice.Triethyl 2-phosphonobutyrate (1.34 g, 5.31 mmol) dissolved in 20 ml ofdehydrated tetrahydrofuran was added dropwise. After completion of thedropwise addition, the mixture was stirred for 1 hour. Next, benzyl5-formyl-2-methoxybenzoate (Referential example 3; 1.44 g, 5.33 mmol)dissolved in 25 ml of dehydrated tetrahydrofuran was added dropwise.After completion of the dropwise addition, the mixture was stirred for4.5 hours at room temperature. The reaction mixture was poured into icewater, which was extracted with ethyl acetate, washed with water andsaturated brine in sequence, then dried over anhydrous sodium sulfateand concentrated. The residue was purified by silica gel chromatography(eluate n-hexane: ethyl acetate=5:1 v/v) to obtain 1.45 g (74%) of ethyl(3-benzyloxy-carbonyl-4-methoxyphenyl)-2-ethylacrylate as a yellow oil.

Mass analysis m/z 368 (M⁺).

The ethyl (3-benzyloxy-carbonyl-4-methoxyphenyl)-2-ethylacrylate (4.00g, 10.9 mmol) was dissolved in 200 ml of ethanol, 10% palladium onactivated carbon (1.10 g) was added, and medium pressure hydrogenationwas performed for 3 hours at an initial pressure of 353 kPa. Aftercompletion of the reaction, the catalyst was filtered and the filtratewas concentrated to obtain 3.0 g (98%) of the title compound as afaintly yellow oil.

Mass analysis m/z 280(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ 0.93(3H,t,J=7.3Hz), 1.18(3H,t,J=7.3 Hz), 1.52-1.59(1H,m), 1.59-1.70(1H, m),2.55-2.61(1H,m), 2.76(1H,dd,J=14.2, 6.4 Hz), 2.92(1H,dd,J=14.2, 6.4 Hz),4.03-4.12(2H,m), 4.06(3H,s), 6.97(1H,d,J=8.8 Hz), 7.38(1H, dd,J=8.8, 2.4Hz), 8.00(1H,d,J=2.4 Hz).

EXAMPLES 2 THROUGH 6

The compounds listed in Table 1 were obtained similarly to Example 1.

TABLE 1

Example R² R⁴ R⁵ Mass analysis (m/z) 2 CH₃ OCH₃ C₂H₅ 266 (M⁺) 3 n-C₃H₇OCH₃ C₂H₅ 294 (M⁺) 4 OCH₃ OCH₃ C₂H₅ 282 (M⁺) 5 OC₂H₅ OCH₃ C₂H₅ 296 (M⁺)6 OPh OCH₃ C₂H₅ 344 (M⁺)

EXAMPLE 7 Ethyl2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]-methyl]carbamoyl]phenyl]propanoate

Ethyl 3-(3-carboxy-4-methoxyphenyl)-2-ethylpropanoate (5.00 g, 17.8mmol) was dissolved in 80 ml of dehydrated dichloroethane, which wascooled to −10° C. to −15° C. Triethylamine (6.21 ml, 44.5 mmol) wasadded under stirring. Next, ethyl chlorocarbonate (1.86 ml, 19.5 mmol),dissolved in 10 ml of dehydrated dichloromethane was added dropwise.After stirring for 10 minutes at −10° C., 4-(trifluoromethyl)benzylamine(2.51 ml, 17.8 mmol), dissolved in 10 ml of dehydrated dichloromethanewas added dropwise.

After stirring for 30 minutes at −10° C., the mixture was stirred for 7hours at room temperature and then allowed to stand overnight. Thereaction mixture was washed with aqueous solution of citric acid,aqueous solution of sodium hydrogencarbonate and brine in sequence, thendried over anhydrous sodium sulfate and concentrated. The residue wasrecrystallized from a mixed solvent of n-hexane with ethyl acetate toobtain 7.2 g (93%) of the aimed compound as colorless crystals. Meltingpoint 77.5-79.5° C.;

Mass analysis m/z 437(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ 0.91(3H,t,J=7.3Hz), 1.18(3H,t,J=7.3 Hz), 1.51-1.69(2H,m), 2.54-2.61(1H,m), 2.75(1H,dd,J=13.7, 6.8 Hz), 2.92(1H,dd,J=13.7, 8.8 Hz), 3.92(3H,s),4.04-4.12(2H,m), 4.73(2H,d,J=5.9 Hz), 6.89(1H,d,J=8.8 Hz),7.25-7.28(1H,m), 7.47(2H,d,J=7.8 Hz), 7.59(2H,d,J=8.3 Hz),8.06(1H,d,J=2.4 Hz), 8.30(1H,t,J=5.4 Hz).

EXAMPLES 8 THROUGH 19

The compounds listed in Table 2 were obtained similarly to Example 7.

TABLE 2

Example R¹ R² R⁴ R⁵ Mass analysis (m/z)  8 4-CF₃ CH₃ OCH₃ C₂H₅ 423 (M⁺) 9 4-OCH₂Ph CH₃ OCH₃ C₂H₅ 461 (M⁺) 10 4-OPh C₂H₅ OCH₃ C₂H₅ 461 (M⁺) 114-OCH₂Ph C₂H₅ OCH₃ C₂H₅ 475 (M⁺) 12 4-Ph C₂H₅ OCH₃ C₂H₅ 445 (M⁺) 134-CF₃ OCH₃ OCH₃ C₂H₅ 439 (M⁺) 14 4-OCH₂Ph OCH₃ OCH₃ C₂H₅ 477 (M⁺) 154-OPh OCH₃ OCH₃ C₂H₅ 463 (M⁺) 16 4-Ph OCH₃ OCH₃ C₂H₅ 447 (M⁺) 17 4-OCH₃OCH₃ OCH₃ C₂H₅ 401 (M⁺) 18 4-CF₃ OC₂H₅ OCH₃ C₂H₅ 453 (M⁺) 19 4-CF₃ OPhOCH₃ C₂H₅ 437 (M⁺)

EXAMPLE 202-Ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]-methyl]carbamoyl]phenyl]propanoicacid

Ethyl2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate(1.26 g, 2.88 mmol; Example 7), 15 ml of ethanol and 15 ml of 1 mol/laqueous solution of sodium hydroxide were mixed and, after stirring for4 hours at 50° C., the reaction mixture was concentrated under reducedpressure. The residue was dissolved in water, which was made acidic withdilute hydrochloric acid. The precipitates produced were filtered, driedand then recrystallized from ethyl acetate to obtain 1.26 g (95%) of thetitle compound as colorless prisms. Melting point 144.5-146.5° C.; Massanalysis m/z 409(M⁺); Elemental analysis C₂₁H₂₂F₃NO₄(409.40):

Calcd. C, 61.61; H, 5.42; N, 3.42.

Found C, 61.48; H, 5.40; N, 3.41.

¹H-NMR (400 MHz, CDCl₃) δ0.96(3H,t,J=7.3 Hz), 1.53-1.72(2H,m),2.59-2.66(1H,m), 2.77(1H,dd,J=13.7, 6.8 Hz), 2.96(1H,dd,J=13.7, 8.3 Hz),3.92(3H,s), 4.73(2H,d,J=5.9 Hz), 6.90(1H,d,J=8.3 Hz), 7.29(1H,dd,J=8.3,2.4 Hz), 7.47(2H,d,J=8.3 Hz), 7.59(2H,d,J=7.8 Hz), 8.08 (1H,d,J=2.4 Hz),8.32(1H,t,J=5.9 Hz).

EXAMPLES 21-31

The compounds listed in Table 3 were obtained similarly to Example 20.

TABLE 3

Example R¹ R² R⁴ Melting point (° C.) Charac. formula Elemental analysis(%) 21 4-OCH₂Ph C₂H₅ OCH₃ 127.0-122.5 C₂₇H₂₉NO₅ Calcd.; C 72.46, H 65.3,N 3.13 Found; C 72.30, H 6.55, N 3.14 22 4-Ph C₂H₅ OCH₃ 158.5-159.5C₂₆H₂₇NO₄ Calcd.; C 74.80, H 6.52, N 3.35 Found; C 74.87, H 6.63, N 3.3423 4-OPh C₂H₅ OCH₃ 127.0-128.0 C₂₈H₂₇NO₅ Calcd.; C 72.04, H 6.28, N 3.23Found; C 71.86, H 6.31, N 3.21 24 4-CF₃ OCH₃ OCH₃ 161.0-163.0C₂₀H₂₀F₃NO₅ Calcd.; C 58.39, H 4.90, N 3.40 Found; C 58.35, H 4.82, N3.49 25 4-OCH₂Ph OCH₃ OCH₃ 136.0-138.0 C₂₆H₂₇NO₆ Calcd.; C 69.47, H6.05, N 3.12 Found; C 69.38, H 6.09, N 3.16 26 4-Ph OCH₃ OCH₃176.0-178.0 C₂₅H₂₅N₅ Calcd.; C 71.58, H 6.01, N 3.34 Found; C 71.56, H6.15, N 3.36 27 4-OPh OCH₃ OCH₃ 137.5-139.0 C₂₅H₂₅NO₆ Calcd.; C 68.95, H5.79, N 3.22 Found; C 68.74, H 5.80, N 3.23 28 4-OCH₃ OCH₃ OCH₃128.5-129.5 C₂₀H₂₃NO₆ Calcd.; C 64.33, H 6.21, N 3.75 Found; C 64.22, H6.22, N 3.79 29 4-CF₃ OC₂H₅ OCH₃ 146.0-148.0 C₂₁H₂₂F₃NO₅ Calcd.; C59.29, H 5.21, N 3.29 Found; C 59.04, H 5.10, N 3.33 30 4-CF₃ CH₃ OCH₃155.0-156.0 C₂₀H₂₀F₃NO₄ Calcd.; C 60.76, H 5.10, N 3.54 Found; C 60.77,H 5.12, N 3.57 31 4-CF₃ OPh OCH₃ 141.5-143.0 C₂₅H₂₂F₃NO₅ Calcd.; C63.42, H 4.68, N 2.96 Found; C 63.25, H 4.70, N 2.93

Referential Example 15-Formyl-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide

Publicly known [e.g. E. J. Wayne et al, J. Chem. Soc., 1022(1922)]5-formyl-2-methoxybenzoic acid (4.05 g, 22.5 mmol) was dissolved in 80ml of dichloromethane, which was cooled with ice. Triethylamine (7.94ml, 56.2 mmol) was added under stirring. Next, ethyl chlorocarbonate(2.44 ml, 24.8 mmol) was added and, after stirring for 10 minutes,4-(trifluoromethyl)benzylamine (3.31 ml, 22.5 mmol) was added dropwise,which was allowed to stand overnight. After washed with water, thereaction mixture was dried over anhydrous sodium sulfate andconcentrated. Water was added to the residue, which was made acidic withdilute hydrochloric acid. Then, the precipitates were filtered and driedto quantitatively obtain the title compound as milky white crystals.

Mass analysis m/z 337(M⁺).

EXAMPLE 32 Ethyl2-methoxy-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]acrylate

Ethyl 2-(diethoxyphosphoryl)-2-methoxyacetate (265 mg, 1.10 mmol) wasdissolved in 3 ml of dehydrated tetrahydrofuran and potassium t-butoxide(123 mg, 1.10 mmol) was added under stirring and cooling with ice underan atmosphere of argon, which was stirred for 30 minutes. Next,N-[[4-(trifluoromethyl)phenyl]methyl]-5-formyl-2-methoxybenzamide (338mg, 1.00 mmol) dissolved in 2 ml of dehydrated tetrahydrofuran wasadded. After stirring for 1 hour at room temperature, the reactionmixture was poured into ice water, which was extracted with ethylacetate, washed with water and brine in sequence, then dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel chromatography (eluate n-hexane:ethyl acetate=3:1 v/v) toobtain 330 mg (78%) of the title compound (mixture of geometricalisomers relevant to double bond) as colorless crystals.

Mass analysis m/z 423(M⁺).

EXAMPLE 33 Ethyl2-methoxy-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate

Ethyl2-methoxy-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]acrylate(150 mg, 0.354 mmol), 2.5 ml of ethanol and 2.5 ml of tetrahydrofuranwere mixed, 10% palladium on activated carbon (30 mg) was added thereto,and normal pressure hydrogenation was conducted for 7.5 hours at roomtemperature. After completion of the reaction, the catalyst was filteredand the filtrate was concentrated to obtain 148 mg (98%) of the titlecompound as colorless crystals.

Mass analysis m/z 425(M⁺).

Referential Example 22-Methoxy-5-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide

Publicly known [e.g. De.Paulis et al, J. Med. Chem.,1022(1922)]2-methoxy-5-nitrobenzoic acid (9.00 g, 45.7 mmol) wasdissolved in 450 ml of dichloromethane and, after triethylamine (8.11ml, 58.4 mmol) and ethyl chlorocarbonate (4.70 ml, 49.3 mmol) wereadded, the mixture was stirred for 45 minutes at room temperature. Next,4-trifluoromethylbenzylamine (9.59 g, 54.8 mmol) was added dropwise,which was stirred for 30 minutes at room temperature. The reactionmixture was poured into water. The organic layer was separated, driedover anhydrous magnesium sulfate and concentrated. The residue wasrecrystallized from ethyl acetate to obtain 12.5 g of the aimed compoundas yellow powder. Further, the filtrate was concentrated andrecrystallized from ethyl acetate to obtain 2.13 g of the secondcrystals. Total 14.6 g (91%).

Mass analysis m/z 354(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ4.09(3H,s),4.75(2H,d,J=5.9 Hz), 7.11(1H,d,J=8.8 Hz), 7.47(2H,d,J=7.8 Hz), 7.61(2H,d,J=7.8 Hz), 8.05(1H,brs), 8.36(1H,dd,J=8.8, 3.0 Hz), 9.12(1H,d,J=3.0 Hz).

EXAMPLE 345-Amino-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide

2-Methoxy-5-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide (14.6g, 41.2 mmol) and 146 ml of ethyl acetate were mixed and, after 10%palladium on activated carbon (2.6 g) was added, the mixture was stirredfor 5 hours at room temperature. Catalyst was filtered, washed withethyl acetate, and the reaction mixture was concentrated. The residuewas recrystallized from a mixed solvent of n-hexane with ethyl acetateto obtain 12.4 g (93%) of the title compound as colorless crystals.

Mass analysis m/z 324(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ3.87(3H,s),4.72(2H,d,J=5.9 Hz), 6.80(1H,dd,J=8.8, 3.0 Hz), 6.83(1H,d,J=8.8 Hz),7.46(2H,d,J=7.8 Hz), 7.59(3H,m), 8.43(1H,brs).

EXAMPLE 35 Ethyl2-bromo-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate

5-Amino-2-methoxy-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamide (7.00g, 21.6 mmol), 85 ml of acetone and 34 ml of methanol were mixed, whichwas cooled with ice. Under stirring, 17.5 ml of 47% hydrobromic acid,sodium nitrite (1.65 g, 23.9 mmol) and 6.2 ml of water were added andthe mixture was stirred for 10 minutes. Next, ethyl acrylate (13.4 ml,128 mmol) and copper oxide (I) (416 mg, 2.91 mmol) were added at roomtemperature. After stirring for 30 minutes, the reaction mixture waspoured into saturated aqueous solution of sodium hydrogencarbonate,which was extracted with ethyl acetate. The extract was washed withbrine, then dried over anhydrous magnesium sulfate and concentrated. Theresidue was recrystallized from a mixed solvent of n-hexane with ethylacetate to obtain 683 mg (71%) of the title compound as colorlesscrystals.

Mass analysis m/z 469(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ1.21-1.26(6H, m),2.61-2.67(2H,m), 2.96(1H,dd,J=14.2, 6.8 Hz), 3.18(1H,dd,J=14.2, 9.3 Hz),3.53(1H,dd,J=9.3, 6.8 Hz), 3.93(3H,s), 4.10-4.19(2H,m), 4.73 (2H,d,J=5.9Hz), 6.91(1H,d,J=8.3 Hz), 7.32(1H,dd,J=8.3, 2.4 Hz), 7.47(2H,d,J=7.8Hz), 7.59(2H,d,J=7.8 Hz), 8.11(1H,d,J=2.4 Hz), 8.30 (1H,brs).

EXAMPLE 36 Ethyl2-ethylthio-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate

Ethyl2-bromo-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate(1.00 g, 2.05 mmol; Example 37) and 56 ml of ethanol were mixed and,after sodium thioethoxide (268 mg, 2.55 mmol) was added under stirring,the mixture was refluxed for 1.5 hours. The reaction mixture wasconcentrated, water was added, and the solution was extracted with ethylacetate. The extract was washed with brine, then dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel chromatography (eluate n-hexane:ethyl acetate=2:1 v/v) to obtain 3.4g (43%) of the title compound as colorless crystals.

Mass analysis m/z 324(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ 3.87(3H,s),4.72(2H,d,J=5.9 Hz), 6.80(1H,dd,J=8.8, 3.0 Hz), 6.83(1H,d,J=8.8 Hz),7.46(2H,d,J=7.8 Hz), 7.59(3H,m), 8.43(1H,brs).

EXAMPLES 37 AND 38

The compounds listed in Table 4 were obtained similarly to Example 36.

TABLE 4

Example R¹ R² R⁴ R⁵ Mass analysis (m/z) 37 4-CF₃ SPh OCH₃ C₂H₅ 517 (M⁺)38 4-CF₃ SCH₂Ph OCH₃ C₂H₅ 531 (M⁺)

EXAMPLES 39 THROUGH 41

Compounds in Table 5 were obtained similarly to Example 20.

Table 5

Example R¹ R² R⁴ Melting point (° C.) Charac. formula Elemental analysis(%) 39 4-CF₃ SC₂H₅ OCH₃ 155.0-157.0 C₂₁H₂₂F₃NO₄S Calcd.; C 57.13, H5.02, N 3.17 Found; C 56.79, H 4.89, N 3.15 40 4-CF₃ SPh OCH₃130.0-131.5 C₂₅H₂₂F₃NO₄S Calcd.; C 61.34, H 4.53, N 2.86 Found; C 61.08,H 4.45, N 2.82 41 4-CF₃ SCH₂Ph OCH₃ Foam C₂₁H₂₂F₃NO₄S Calcd.; C 62.02, H4.80, N 2.78 Found; C 62.39, H 5.03, N 2.72

Referential Example 3 Benzyl 5-acetoxymethyl-2-methoxybenzoate

5-Formyl-2-methoxybenzoic acid (1.76 g, 9.77 mmol), benzylbromide (1.26ml, 10.3 mmol), potassium hydrogencarbonate (2.94 g, 29.3 mmol) and 40ml of N,N-dimethylformamide were mixed and the mixture was stirred for 4hours at room temperature, then the insolubles were filtered. Ethylacetate was added to the filtrate, which was washed with water and withbrine, then dried over anhydrous sodium sulfate and concentrated toquantitatively obtain benzyl 5-formyl-2-methoxybenzoate.

Mass analysis m/z 270(M⁺); Melting point 58.5-59.5° C.

Benzyl 5-formyl-2-methoxybenzoate (1.10 g, 4.07 mmol) and 30 ml ofmethanol were mixed and sodium borohydride (155 mg, 4.10 mmol) was addedlittle by little under stirring and cooling with ice. After stirring for2 hours under cooling with ice, the reaction mixture was poured into icewater and made acidic with 1 mol/l hydrochloric acid, which wasextracted with ethyl acetate. The extract was washed with water and withbrine, then dried over anhydrous sodium sulfate and concentrated toobtain 1.11 g (99%) of benzyl 5-hydroxymethyl-2-methoxybenzoate (withoutpurifying further, this compound was used for the next reaction).

Next, benzyl 5-hydroxymethyl-2-methoxybenzoate and 100 ml of methylenechloride were mixed and, after pyridine (660 ml, 8.16 mmol), aceticanhydride (460 ml, 4.88 mmol) and N,N-dimethylaminopyridine (25 mg,0.205 mmol) were added under stirring and cooling with ice, the mixturewas stirred overnight. The reaction mixture was washed with 1 mol/lhydrochloric acid, aqueous solution of sodium hydrogencarbonate andbrine, then dried over anhydrous sodium sulfate and concentrated toobtain 1.27 g (99%) of the title compound as a colorless oil.

Mass analysis m/z 314(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ2.08(3H,s),3.91(3H,s), 5.03(2H,s), 5.35(2H,s), 6.97(1H,d,J=8.3 Hz), 7.31-7.50(6H,m), 7.83(1H,d,J=2.4 Hz).

EXAMPLE 42 Methyl3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2,2-dimethylpropanoate

Benzyl 5-acetoxymethyl-2-methoxybenzoate (630 mg, 2.00 mmol), methyltrimethylsilyldimethylketeneacetal (730 mg, 4.02 mmol) and 25 ml ofdehydrated methylene chloride were mixed and magnesium perchlorate (45mg, 0.202 mmol) was added under an atmosphere of argon, which wasstirred for 6 hours at room temperature. The reaction mixture was washedwith water and with brine, then dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluate n-hexane:ethyl acetate=8:1 v/v) to obtain 131 mg (18%) of thetitle compound as colorless crystals.

Mass analysis m/z 356(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ1.16(6H,s),2.79(2H,s), 3.56(3H,s), 3.88(3H,s), 5.33(2H,s), 6.88(1H,d,J=8.8 Hz),7.20(1H,dd,J=8.3, 2.4 Hz), 7.30-7.47(5H,m), 7.56(1H,d,J=2.4 Hz).

EXAMPLE 43 Methyl 3-(3-carboxy-4-methoxyphenyl)-2,2-dimethylpropionate

Methyl 3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2,2-dimethylpropanoate(310 mg, 0.870 mmol) was dissolved in 7 ml of mixed solvent of ethanolwith tetrahydrofuran at a ratio of 1:1, 10% palladium on activatedcarbon (20 mg) was added thereto, and normal pressure hydrogenation wasconducted for 5 hours. After completion of the reaction, catalyst wasfiltered and the filtrate was concentrated to obtain 290 mg (90%) of thetitle compound as a colorless oil.

Mass analysis m/z 266(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ1.18(6H,s),2.85(2H,s), 3.68(3H,s), 4.06(3H,s), 6.96(1H,d,J=8.3 Hz),7.31(1H,dd,J=8.3,2.0 Hz), 7.94(1H,d,J=2.0 Hz), 10.46-11.00(1H,brs).

EXAMPLE 44 Methyl3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]-2,2-dimethylpropanoate

Using methyl 3-(3-carboxy-4-methoxyphenyl)-2,2-dimethylpropanoate (204mg, 0.766 mmol), triethylamine (135 ml, 0.969 mmol), ethylchlorocarbonate (82.0 ml, 0.843 mmol), 4-(trifluoromethyl)benzylamine(120 ml, 0.842 mmol) and 8 ml of dehydrated dichloromethane andconducting the procedure similar to Example 7, 309 mg (95%) of the titlecompound were obtained as a colorless oil.

Mass analysis m/z 423(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ1.18(6H,s),2.85(2H,s), 3.69(3H,s), 3.92(3H,s), 4.73(2H,d,J=5.9 Hz), 6.89(1H,d,J=8.3Hz), 7.20(1H,dd,J=8.3, 2.4 Hz), 7.47(2H,d,J=7.8 Hz), 7.59(2H, d,J=7.8Hz), 7.99(1H,d,J=2.4 Hz), 8.29(1H,brs).

EXAMPLE 453-[4-Methoxy-3-[N-[[4-(trifluoromethyl)phenyl]-methyl]carbamoyl]phenyl]-2,2-dimethylpropanoicacid

Using methyl3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]-2,2-dimethylpropanoate(300 mg, 0.708 mmol; Example 47), ethanol (5 ml) and 10% aqueoussolution of sodium hydroxide (2 ml) and conducting the procedure similarto Example 22, 206 mg (90%) of the title compound were obtained ascolorless crystals.

Melting point 151.0-152.0° C.; Mass analysis m/z 409(M⁺);

Elemental analysis C₂₁H₂₂F₃NO₄ (409.40):

Calcd. C, 61.61; H, 5.42; N, 3.42.

Found C, 61.68; H, 5.45; N, 3.48.;

¹H-NMR (400 MHz, DMSO-d₆) δ1.06(6H,s), 2.96(2H,s), 3.88(3H,s), 4.56(2H,d,J=6.4 Hz), 7.06(1H,d,J=8.8 Hz), 7.25(1H,dd,J=8.8, 2.4 Hz),7.51-7.58(2H,m), 7.70(1H,d,J=7.8 Hz), 8.80(1H,t,J=5.9 Hz), 12.24(1H, s).

Referential Example 4 (S)-4-benzyl-3-butyryl-2-oxazolidinone

(S)-4-benzyl-2-oxazolidinone (2.26 g, 15.0 mmol) and 30 ml of dehydratedtetrahydrofuran were mixed, which was cooled to −78° C. under anatmosphere of argon. Under stirring, 1.6 mol/l solution of n-butyllithium in hexane (10.3 ml, 16.5 mmol) was added dropwise for over 10minutes and the mixture was stirred for 30 minutes as it was. Next,butyryl chloride (1.56 ml, 15.0 mmol) dissolved into 30 ml of dehydratedtetrahydrofuran was added dropwise for over 10 minutes and the mixturewas stirred for 30 minutes, followed by stirring for 3 hours at roomtemperature. Saturated aqueous solution of ammonium chloride was addedto the reaction mixture and concentrated. Water was added to theresidue, which was extracted with ethyl acetate. The extract was washedwith water and with brine, then dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 3.64 g (98%) of thetitle compound as a colorless oil.

Mass analysis m/z 247(M⁺).

EXAMPLE 46(+)-2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoicacid

(S)-4-benzyl-3-butyryl-2-oxazolidinone (1.65 g, 6.68 mmol) was dissolvedin 22 ml of dehydrated methylene chloride, which was cooled to −74° C.under an atmosphere of argon. After triethylamine (1.11 ml, 8.02 mmol)was added, 1.0 mol/l solution of dibutylboryltrifurate in methylenechloride (7.35 ml, 7.35 mmol) was added dropwise over 15 minutes, whichwas stirred for 30 minutes. Next, after stirring for 50 minutes undercooling with ice, the mixture was cooled to −75° C. Following this,benzyl 5-formyl-2-methoxybenzoate (1.81 g, 6.68 mmol) dissolved into56.5 ml of dehydrated methylene chloride was added dropwise over 20minutes. After stirring for 1.5 hours at −75° C., the mixture wasstirred for 2 hours under cooling with ice. A mixed solution comprising30 ml of methanol, 16.7 ml of phosphate buffer and 7.3 ml of 30% aqueoushydrogen peroxide was added and the mixture was stirred further for 30minutes at 0° C. The reaction mixture was poured into water, which wasextracted with methylene chloride. The extract was washed with brine,then dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel chromatography (eluate n-hexane:ethylacetate=3:2 v/v) to obtain 1.36 g (39%) of(4S)-3-[3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2-ethyl-3-hydroxypropionyl]-4-benzyl-2-oxazolidinone.

Mass analysis m/z 518(M+1)⁺.

Next,(4S)-3-[3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2-ethyl-3-hydroxypropionyl]-4-benzyl-2-oxazolidinone(1.35 g, 2.61 mmol) and 22 ml of trifluoroacetic acid were mixed undercooling with ice and triethylsilane (3.95 ml, 26.1 mmol) was added over5 minutes. The mixture was stirred for 1 hour under cooling with ice,followed by stirring for 4 days at room temperature. The reactionmixture was concentrated and the residue was poured into 0.5 mol/laqueous solution of sodium hydroxide, which was washed with ethylacetate. The aqueous layer was made acidic and extracted with methylenechloride. The extract was washed with brine, then dried over anhydrousmagnesium sulfate and concentrated to obtain 1.34 g of crude(4S)-3-[3-(3-carboxy-4-methoxyphenyl)-2-ethylpropionyl]-4-benzyl-2-oxazolidinoneas a yellow oil. This compound was used for next reaction withoutpurifying further.

Using crude(4S)-3-[3-(3-carboxy-4-methoxyphenyl)-2-ethylpropionyl]-4-benzyl-2-oxazolidinone(1.34 g), triethylamine (435 ml, 3.13 mmol), ethyl chlorocarbonate (275ml, 2.87 mmol), 4-(trifluoromethyl)benzylamine (686 mg, 3.92 mmol) and33 ml of methylene chloride and conducting the procedure similar toExample 7, 860 mg (58%) of(4S)-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]-carbamoyl]phenyl]propionyl]-4-benzyl-2-oxazolidinoneas colorless powder.

Mass analysis m/z 568(M⁺); ¹H-NMR (400 MHz, CDCl₃) δ 0.98(3H,t,J=7.3Hz), 1.58-1.65(1H,m), 1.80-1.87(1H,m), 2.71(1H,dd,J=13.2, 9.8 Hz),2.78(1H,dd,J=13.2, 6.4 Hz), 3.00(1H,dd,J=13.7, 8.3 Hz),3.30(1H,dd,J=13.7, 2.9 Hz), 3.92(3H,s), 3.98-4.07(3H,m), 4.61-4.67(1H,m), 4.71(2H,d,J=5.9 Hz), 6.90(1H,d,J=8.3 Hz), 7.20-7.37(6H,m),7.44(2H,d,J=7.8 Hz), 7.57(2H,d,J=7.8 Hz), 8.00(1H,d,J=2.5 Hz),8.24(1H,t,J=5.9 Hz).

(4S)-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propionyl]-4-benzyl-2-oxazolidinone(860 mg, 1.51 mmol) was mixed with 8 ml of mixed solution oftetrahydrofuran with water (4:1 v/v), which was cooled with ice under anatmosphere of argon. Under stirring, 611 ml of 30% aqueous hydrogenperoxide was added over 2 minutes, further 101 mg of lithium hydroxidemonohydrate dissolved in 2.7 ml of water was added thereto over 2minutes. After the mixture was stirred for 1 hour under cooling withice, sodium sulfite 7-hydrate dissolved in 4 ml of water was added, andthe mixture was stirred for 5 minutes at 0° C. The reaction mixture waspoured into 5% aqueous solution of hydrochloric acid, which wasextracted with ethyl acetate. The extract was washed with brine, thendried over anhydrous magnesium sulfate and concentrated. The residue wascrystallized by adding ethyl acetate and n-hexane to obtain 125 mg (20%)of the title compound as colorless prisms.

Melting point 128.0-130.0° C.; Mass analysis m/z 409(M⁺);

Elemental analysis C₂₁H₂₂F₃NO₄ (409.40):

Calcd. C, 61.61; H, 5.42; N, 3.42.

Found C, 61.48; H, 5.40; N, 3.41.;

¹H-NMR (400 MHz, CDCl₃) δ0.96(3H,t,J=7.3 Hz), 1.55-1.71(2H,m),2.61-2.67(1H,m), 2.77(1H,dd,J=13.7, 6.4 Hz), 2.96(1H,dd,J=13.7, 7.8 Hz),3.92(3H,s), 4.73(2H,d,J=5.9 Hz), 6.90(1H,d,J=8.3 Hz), 7.29 (1H,dd,J=8.3,2.4 Hz), 7.46 (2H,d,J=8.3 Hz), 7.59(2H,d,J=8.3 Hz), 8.08(1H,d,J=2.4 Hz),8.32(1H,t,J=5.9 Hz).

Specific rotation [α]_(D) ²⁵+23°(C 0.4, MeOH); Optical purity 88% e.e.(from HPLC analysis using Chiral PAC AD).

EXAMPLES 47 AND 48

The compounds listed in Table 6 were obtained similarly to Example 1.

TABLE 6

Example R² R⁴ R⁵ Mass analysis (m/z) 47 i-C₃H₇ OCH₃ C₂H₅ 294 (M⁺) 48n-C₄H₉ OCH₃ C₂H₅ 308 (M⁺)

EXAMPLES 49 THROUGH 94

The compounds listed in Table 7 were obtained similarly to Example 7.

TABLE 7

Mass analysis Example R¹ R² R⁴ R⁵ (m/z) 49 4-CF₃ n-C₃H₇ OCH₃ C₂H₅ 451(M⁺) 50 4-OPh n-C₃H₇ OCH₃ C₂H₅ 475 (M⁺) 51 4-OCH₂Ph n-C₃H₇ OCH₃ C₂H₅ 489(M⁺) 52 4-Ph n-C₃H₇ OCH₃ C₂H₅ 459 (M⁺) 53 4-CF₃ i-C₃H₇ OCH₃ C₂H₅ 451(M⁺) 54 4-OPh i-C₃H₇ OCH₃ C₂H₅ 475 (M⁺) 55 4-OCH₂Ph i-C₃H₇ OCH₃ C₂H₅ 489(M⁺) 56 4-Ph i-C₃H₇ OCH₃ C₂H₅ 459 (M⁺) 57 4-CF₃ n-C₄H₉ OCH₃ C₂H₅ 465(M⁺) 58 4-OPh n-C₄H₉ OCH₃ C₂H₅ 489 (M⁺) 59 4-OCH₂Ph n-C₄H₉ OCH₃ C₂H₅ 503(M⁺) 60 4-Ph n-C₄H₉ OCH₃ C₂H₅ 473 (M⁺) 61 2-OPh C₂H₅ OCH₃ C₂H₅ 461 (M⁺)62 3-OPh C₂H₅ OCH₃ C₂H₅ 461 (M⁺) 63 2-OPh n-C₃H₇ OCH₃ C₂H₅ 475 (M⁺) 643-OPh n-C₃H₇ OCH₃ C₂H₅ 475 (M⁺) 65 4-OPh(4-CH₃) C₂H₅ OCH₃ C₂H₅ 475 (M⁺)66 4-OPh(3-CH₃) C₂H₅ OCH₃ C₂H₅ 475 (M⁺) 67 4-OPh(2-CH₃) C₂H₅ OCH₃ C₂H₅475 (M⁺) 68 4-OPh(4-Cl) C₂H₅ OCH₃ C₂H₅ 495 (M⁺) 69 4-OPh(3-Cl) C₂H₅ OCH₃C₂H₅ 495 (M⁺) 70 4-OPh(4-F) C₂H₅ OCH₃ C₂H₅ 479 (M⁺) 71 4-OPh(4-Br) C₂H₅OCH₃ C₂H₅ 539 (M⁺) 72 4-OPh(4-OCH₃) C₂H₅ OCH₃ C₂H₅ 491 (M⁺) 734-OPh(3-OCH₃) C₂H₅ OCH₃ C₂H₅ 491 (M⁺) 74 4-OPh(2-OCH₃) C₂H₅ OCH₃ C₂H₅491 (M⁺) 75 4-OPh(4-CH₃) n-C₃H₇ OCH₃ C₂H₅ 489 (M⁺) 76 4-OPh(3-CH₃)n-C₃H₇ OCH₃ C₂H₅ 489 (M⁺) 77 4-OPh(2-CH₃) n-C₃H₇ OCH₃ C₂H₅ 489 (M⁺) 784-OPh(3-Cl) n-C₃H₇ OCH₃ C₂H₅ 509 (M⁺) 79 4-OPh(4-OCH₃) n-C₃H₇ OCH₃ C₂H₅505 (M⁺) 80 4-OPh(3-OCH₃) n-C₃H₇ OCH₃ C₂H₅ 505 (M⁺) 81 4-OPh(2-OCH₃)n-C₃H₇ OCH₃ C₂H₅ 505 (M⁺) 82 4-OPh(4-F) n-C₃H₇ OCH₃ C₂H₅ 493 (M⁺) 834-OPh(4-Br) n-C₃H₇ OCH₃ C₂H₅ 553 (M⁺) 84 4-OCF₃ n-C₃H₇ OCH₃ C₂H₅ 467(M⁺) 85 4-CH₃ n-C₃H₇ OCH₃ C₂H₅ 397 (M⁺) 86 4-OCH₃ n-C₃H₇ OCH₃ C₂H₅ 413(M⁺) 87 4-Ph(4-Cl) n-C₃H₇ OCH₃ C₂H₅ 493 (M⁺) 88 4-Ph(4-CH₃) n-C₃H₇ OCH₃C₂H₅ 473 (M⁺) 89 4-Ph(4-OCH₃) n-C₃H₇ OCH₃ C₂H₅ 489 (M⁺) 904-OCH₂Ph(4-Cl) n-C₃H₇ OCH₃ C₂H₅ 523 (M⁺) 91 4-OCH₂Ph(4-CH₃) n-C₃H₇ OCH₃C₂H₅ 503 (M⁺) 92 4-OPh(2-F) n-C₃H₇ OCH₃ C₂H₅ 493 (M⁺) 93 4-OPh(2-OC₂H₅)n-C₃H₇ OCH₃ C₂H₅ 519 (M⁺) 94 4-OPh(2-C₂H₅) n-C₃H₇ OCH₃ C₂H₅ 503 (M⁺)

EXAMPLE 95 THROUGH 141

The compounds listed in Table 8 were obtained similarly to Example 20.

TABLE 8

Example R¹ R² R⁴ Melting point (° C.) Charac. formula Elemental analysis(%)  95 4-CF₃ n-C₃H₇ OCH₃ 147 C₂₂H₂₄F₃NO₄ Calcd.; C 62.40, H 5.71, N3.31 Found; C 62.33, H 5.65, N 3.39  96 4-OPh n-C₃H₇ OCH₃ 117 C₂₇H₂₉NO₅Calcd.; C 72.46, H 6.53, N 3.13 Found; C 72.31, H 6.56, N 3.28  974-OCH₂Ph n-C₃H₇ OCH₃ 111-112 C₂₈H₃₁NO₅ Calcd.; C 72.86, H 6.77, N 3.03Found; C 72.77, H 6.76, N 3.10  98 4-Ph n-C₃H₇ OCH₃ 160-162C₂₇H₂₈NO₄.1/10H₂O Calcd.; C 74.84, H 6.79, N 3.23 Found; C 74.76, H6.81, N 3.37  99 4-CF₃ i-C₃H₇ OCH₃ 174-175 C₂₂H₂₄F₃NO₄ Calcd.; C 62.40,H 5.71, N 3.31 Found; C 62.42, H 5.81, N 3.34 100 4-OPh i-C₃H₇ OCH₃146-147 C₂₇H₂₈NO₅ Calcd.; C 72.46, H 6.53, N 3.13 Found; C 72.43, H6.60, N 3.15 101 4-OCH₂Ph i-C₃H₇ OCH₃ 139-140 C₂₈H₃₁NO₅ Calcd.; C 72.86,H 6.77, N 3.03 Found; C 72.75, H 6.75, N 3.07 102 4-Ph i-C₃H₇ OCH₃ 157C₂₇H₂₈NO₄ Calcd.; C 75.15, H 6.77, N 3.25 Found; C 75.02, H 6.75, N 3.22103 4-CF₃ n-C₄H₉ OCH₃ 150 C₂₃H₂₈F₃NO₄ Calcd.; C 63.15, H 5.99, N 3.20Found; C 63.25, H 5.95, N 3.28 104 4-OPh n-C₄H₉ OCH₃ 141-143 C₂₈H₃₁NO₅Calcd.; C 72.86, H 6.77, N 3.03 Found; C 72.69, H 6.82, N 3.05 1054-OCH₂Ph n-C₄H₉ OCH₃ 137-138 C₂₉H₃₃NO₅.{fraction (1/10)}H₂O Calcd.; C72.96, H 7.01, N 2.93 Found; C 72.85, H 7.01, N 2.99 106 4-Ph n-C₄H₉OCH₃ 135-136 C₂₈H₃₁NO₄ Calcd.; C 75.48, H 7.01, N 3.14 Found; C 75.33, H7.02, N 3.23 107 4-OPh(4-CH₃) C₂H₅ OCH₃ 126-127 C₂₇H₂₉NO₅ Calcd.; C72.46, H 6.53, N 3.13 Found; C 72.27, H 6.53, N 3.10 108 4-OPh(3-CH₃)C₂H₅ OCH₃ 120-121 C₂₇H₂₉NO₅ Calcd.; C 72.46, H 6.53, N 3.13 Found; C72.47, H 6.48, N 3.10 109 4-OPh(2-CH₃) C₂H₅ OCH₃ 142-143 C₂₇H₂₉NO₅Calcd.; C 72.46, H 6.53, N 3.13 Found; C 72.46, H 6.53, N 3.13 1104-OPh(4-Cl) C₂H₅ OCH₃ 143-144 C₂₆H₂₆ClNO₅ Calcd.; C 66.73, H 5.60, N2.99 Found; C 66.52, H 5.64, N 2.97 111 4-OPh(3-Cl) C₂H₅ OCH₃ 131-132C₂₆H₂₆ClNO₅ Calcd.; C 66.73, H 5.60, N 2.99 Found; C 66.68, H 5.56, N3.00 112 4-OPh(4-F) C₂H₅ OCH₃ 137-139 C₂₆H₂₆FNO₅ Calcd.; C 69.17, H5.80, N 3.10 Found; C 69.09, H 5.85, N 3.12 113 4-OPh(4-Br) C₂H₅ OCH₃148-149 C₂₆H₂₆BrNO₅ Calcd.; C 60.95, H 5.11, N 2.73 Found; C 61.02, H5.09, N 2.78 114 4-OPh(4-OCH₃) C₂H₅ OCH₃ 124-125 C₂₇H₂₉NO₆ Calcd.; C69.96, H 6.31, N 3.02 Found; C 69.68, H 6.29, N 3.06 115 4-OPh(3-OCH₃)C₂H₅ OCH₃ 112-113 C₂₇H₂₉NO₆ Calcd.; C 69.96, H 6.31, N 3.02 Found; C69.75, H 6.25, N 3.04 116 4-OPh(2-OCH₃) C₂H₅ OCH₃ 124-125C₂₇H₂₉NO₆.{fraction (1/10)}H₂O Calcd.; C 69.69, H 6.33, N 3.01 Found; C69.53, H 6.32, N 2.93 117 4-OPh(4-CH₃) n-C₃H₇ OCH₃ 139-141 C₂₈H₃₁NO₅Calcd.; C 72.86, H 6.77, N 3.03 Found; C 72.63, H 6.78, N 3.10 1184-OPh(3-CH₃) n-C₃H₇ OCH₃ 102-103 C₂₉H₃₁NO₆.{fraction (1/10)}H₂O Calcd.;C 72.58, H 6.79, N 3.02 Found; C 72.41, H 6.82, N 3.02 119 4-OPh(2-CH₃)n-C₃H₇ OCH₃ 114 C₂₈H₃₁NO₅ Calcd.; C 72.86, H 6.77, N 3.03 Found; C72.83, H 6.83, N 3.12 120 4-OPh(3-Cl) n-C₃H₇ OCH₃ 101-102 C₂₇H₂₈ClNO₅Calcd.; C 67.28, H 5.86, N 2.91 Found; C 67.23, H 5.80, N 2.90 1214-OPh(4-OCH₃) n-C₃H₇ OCH₃ 124-125 C₂₈H₃₁NO₆ Calcd.; C 70.42, H 6.54, N2.93 Found; C 70.36, H 6.57, N 2.99 122 4-OPh(3-OCH₃) n-C₃H₇ OCH₃ 92-93C₂₈H₃₁NO₆ Calcd.; C 70.42, H 6.54, N 2.93 Found; C 70.13, H 6.64, N 2.87123 4-OPh(2-OCH₃) n-C₃H₇ OCH₃ 124-125 C₂₈H₃₁NO₆.{fraction (1/10)}H₂OCalcd.; C 70.16, H 6.56, N 2.92 Found; C 70.07, H 6.61, N 2.92 1244-OPh(4-F) n-C₃H₇ OCH₃ 148-149 C₂₇H₂₈FNO₆ Calcd.; C 69.66, H 6.06, N3.01 Found; C 69.36, H 6.06, N 3.02 125 4-OPh(4-Br) n-C₃H₇ OCH₃ 153-154C₂₇H₂₇BrNO₆ Calcd.; C 61.60, H 5.36, N 2.66 Found; C 61.57, H 5.31, N2.70 126 4-OCF₃ n-C₃H₇ OCH₃ 126-127 C₂₂H₂₄F₃NO₆ Calcd.; C 60.13, H 5.51,N 3.19 Found; C 59.86, H 5.50, N 3.16 127 4-CH₃ n-C₃H₇ OCH₃ 115-116C₂₂H₂₇NO₄ Calcd.; C 71.52, H 7.37, N 3.79 Found; C 71.30, H 7.36, N 3.74128 4-OCH₃ n-C₃H₇ OCH₃ 149-150 C₂₂H₂₇NO₅.{fraction (1/10)}H₂O Calcd.; C68.23, H 7.08, N 3.62 Found; C 68.21, H 7.10, N 3.60 129 4-Ph(4-Cl)n-C₃H₇ OCH₃ 163-164 C₂₇H₂₈ClNO₄ Calcd.; C 69.59, H 6.06, N 3.01 Found; C69.55, H 6.03, N 3.03 130 4-Ph(4-CH₃) n-C₃H₇ OCH₃ 155-156 C₂₈H₃₁NO₄Calcd.; C 75.48, H 7.01, N 3.14 Found; C 75.46, H 7.05, N 3.10 1314-Ph(4-OCH₃) n-C₃H₇ OCH₃ 146-147 C₂₆H₃₁NO₆ Calcd.; C 72.86, H 6.77, N3.03 Found; C 72.77, H 6.77, N 3.01 132 4-OCH₂Ph(4-Cl) n-C₃H₇ OCH₃128-129 C₂₉H₃₀ClNO₅ Calcd.; C 67.80, H 6.10, N 2.82 Found; C 67.78, H6.05, N 2.85 133 4-OCH₂Ph(4-CH₃) n-C₃H₇ OCH₃ 118-119 C₂₉H₃₃NO₅ Calcd.; C73.24, H 6.99, N 2.95 Found; C 73.11, H 6.90, N 2.96 134 4-CF₃ C₂H₅OC₂H₅ 119-120 C₂₂H₂₄F₃NO₄ Calcd.; C 62.40, H 5.71, N 3.31 Found; C62.33, H 5.70, N 3.32 135 2-OPh C₂H₅ OCH₃ 146-147 C₂₆H₂₇NO₆ Calcd.; C72.04, H 6.28, N 3.23 Found; C 71.90, H 6.32, N 3.23 136 2-OPh n-C₃H₇OCH₃ 111-113 C₂₇H₂₉NO₆ Calcd.; C 72.46, H 6.53, N 3.13 Found; C 72.53, H6.49, N 3.11 137 3-OPh C₂H₅ OCH₃ 91-92 C₂₆H₂₇NO₆ Calcd.; C 72.04, H6.28, N 3.23 Found; C 71.93, H 6.24, N 3.29 138 3-OPh n-C₃H₇ OCH₃111-112 C₂₇H₂₉NO₅ Calcd.; C 72.46, H 6.53, N 3.13 Found; C 72.40, H6.59, N 3.17 139 4-OPh(2-F) n-C₃H₇ OCH₃ 105-106 C₂₇H₂₈FNO₅ Calcd.; C69.66, H 6.06, N 3.01 Found; C 69.66, H 6.05, N 3.05 140 4-OPh(2-OC₂H₅)n-C₃H₇ OCH₃ 121-123 C₂₉H₃₂.{fraction (1/10)}H₂O Calcd.; C 70.60, H 6.78,N 2.84 Found; C 70.33, H 6.78, N 2.84 141 4-OPh(2-C₂H₅) n-C₃H₇ OCH₃113-115 C₂₉H₃₃NO₅ Calcd.; C 73.24, H 6.99, N 2.95 Found; C 73.10, H6.98, N 3.04

EXAMPLES 142 THROUGH 144

The compounds listed in Table 9 were obtained similarly to Example 42.

TABLE 9

Example R² R³ R⁴ R⁵ Mass analysis (m/z) 142 CH₃ C₂H₅ OCH₃ C₂H₅ 384 (M⁺)143 C₂H₅ C₂H₅ OCH₃ C₂H₅ 398 (M⁺) 144 CH₂CF₃ H OCH₃ C₂H₅ 424 (M⁺)

EXAMPLES 145 THROUGH 147

The compounds listed in Table 10 were obtained similarly to Example 43.

TABLE 10

Example R² R³ R⁴ R⁵ Mass analysis (m/z) 145 CH₃ C₂H₅ OCH₃ C₂H₅ 294 (M⁺)146 C₂H₅ C₂H₅ OCH₃ C₂H₅ 308 (M⁺) 147 CH₂CF₃ H OCH₃ C₂H₅ 334 (M⁺)

EXAMPLES 148 THROUGH 153

The compounds listed in Table 11 were obtained similarly to Example 44.

TABLE 11

Mass Example R¹ R² R³ R⁴ R⁵ analysis (m/z) 148 4-CF₃ C₂H₅ C₂H₅ OCH₃ C₂H₅465 (M⁺) 149 4-OPh C₂H₅ C₂H₅ OCH₃ C₂H₅ 489 (M⁺) 150 4-CF₃ CH₃ C₂H₅ OCH₃C₂H₅ 451 (M⁺) 151 4-OPh CH₃ C₂H₅ OCH₃ C₂H₅ 475 (M⁺) 152 4-CF₃ CH₂CF₃ HOCH₃ C₂H₅ 491 (M⁺) 153 4-OPh CH₂CF₃ H OCH₃ C₂H₅ 515 (M⁺)

EXAMPLES 154 THROUGH 159

The compounds listed in Table 12 were obtained similarly to Example 20.

TABLE 12

Example R¹ R² R³ R⁴ Melting point (° C.) Charac. formula Elementalanalysis (%) 154 4-CF₃ C₂H₅ C₂H₅ OCH₃ 156-157 C₂₃H₂₅F₂NO₄ Calcd.; C63.15, H 5.99, N 3.20 Found; C 63.04, H 5.93, N 3.16 155 4-OPh C₂H₅ C₂H₅OCH₃ 144-145 C₂₈H₃₁NO₆.¼H₂O Calcd; C 72.16, H 6.81, N 3.01 Found; C72.04, H 6.81, N 3.07 156 4-CF₃ CH₃ C₂H₅ OCH₃ 167-168 C₂₂H₂₄F₃NO₄Calcd.; C 62.40, H 5.71, N 3.31 Found; C 62.33, H 5.78, N 3.30 157 4-OPhCH₃ C₂H₅ OCH₃ 142-143 C₂₇H₂₉NO₆ Calcd.; C 72.46, H 6.53, N 3.13 Found; C72.38, H 6.43, N 3.09 158 CF₃ CH₂CF₃ H OCH₃ 120-121 C₂₁H₁₉F₆NO₄ Calcd.;C 54.43, H 4.13, N 3.02 Found; C 54.37, H 4.19, N 3.07 159 4-OPh CH₂CF₃H OCH₃ 119-120 C₂₆H₂₄F₃NO₆ Calcd.; C 64.06, H 4.96, N 2.87 Found; C63.96, H 5.04, N 2.90

EXAMPLE 160[3(2S),4S]-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propionyl]-4-benzyloxazolidine-2-one

(±)-2-Ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]-methyl]carbamoyl]phenyl]propanoicacid (Japanese Patent Application No. Hei 11-162235) (26.8 g, 65.6 mmol)and 34 ml of dehydrated tetrahydrofuran were mixed under an atmosphereof argon and triethylamine (9.14 ml, 65.8 mmol) and pivaloyl chloride(8.07 ml, 65.6 mmol) were added dropwise under stirring and cooling withice, which was thereafter stirred for 1.5 hours at room temperature tosynthesize the mixed acid anhydride derivative. On the other hand, inanother vessel, potassium t-butoxide (8.83 g, 78.7 mmol) and 88 ml ofdehydrated tetrahydrofuran were mixed under an atmosphere of argon and(S)-4-benzyloxazolidine-2-one (13.9 g, 78.7 mmol) dissolved into 70 mlof dehydrated tetrahydrofuran was added dropwise. After completion ofthe dropwise addition, the mixture was stirred for 45 minutes. Next, thesuspension of the mixed acid anhydride derivative previously synthesizedwas added dropwise, while filtering under an atmosphere of argon. Aftercompletion of the dropwise addition, the reaction mixture wasconcentrated and then poured into water, which was extracted with ethylacetate. The extract was washed with 5% hydrochloric acid, saturatedsodium hydrogencarbonate and brine in sequence, then dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel chromatography (eluate n-hexane:ethyl acetate=3:2 v/v,then methylene chloride: methanol=15:1 v/v) to obtain 15.2 g (41%) ofthe diastereomer mixture. Diisopropyl ether and ether were added to thismixture, which was dissolved by heating, and then allowed to stand. Theprecipitated crystals were collected by filtration, washed withdiisopropyl ether and then dried to obtain 5.62 g (15%) of the aimedcompound as colorless crystals.

Mass analysis m/z 568(M⁺).

EXAMPLE 161(S)-(+)-2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoicacid

[3(2S),4S]-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propionyl]-4-benzyloxazolidine-2-one(90.9 g, 0.160 mol) was dissolved into 802 ml of mixed solvent oftetrahydrofuran with water (4:1 v/v), which was cooled with ice under anatmosphere of argon. Under stirring, 30% aqueous hydrogen peroxide (63.7ml, 0.630 mol) was added dropwise over 5 minutes. Following this,lithium hydroxide monohydrate (10.7 g, 0.256 mol) dissolved in 267 ml ofwater was added dropwise over 5 minutes and the mixture was stirredfurther for 1 hour under cooling with ice. 64% Sodium hydrogensulfite(102 g, 0.627 mol) dissolved in 401 ml of water was added dropwise tothe reaction mixture. The reaction mixture was concentrated, the residuewas poured into ice water, which was made acidic by adding 5%hydrochloric acid, and then extracted with methylene chloride. Theextract was washed with brine, then dried over anhydrous magnesiumsulfate and concentrated. The residue was dissolved in ethyl acetate andn-hexane by heating and allowed to stand. The precipitated crystals werecollected by filtration and dried. Additionally, second crystals wereobtained from the filtrate. The first crystals and the second crystalswere combined, washed with mixed solvent of n-hexane with ethyl acetate(4:1 v/v) in suspended state, and then dried to obtain 52.4 g (80%) ofthe aimed compound as colorless crystalline powder.

Melting point 128-130° C.;

Mass analysis m/z 409(M⁺);

Elemental analysis C₂₁H₂₂F₃NO₄ (409.40):

Calcd. C, 61.61; H, 5.42; N, 3.42.

Found C, 61.41; H, 5.44; N, 3.41.;

¹H-NMR (400 MHz, CDCl₃) δ0.95(3H,dd,J=7.3, 7.3 Hz), 1.54-1.70(2H, m),2.58-2.65(1H,m), 2.77(1H,dd,J=13.7, 6.3 Hz), 2.96(1H,dd,J=13.7, 8.3 Hz),3.92(3H,s), 4.38(1H,brs), 4.72(2H,d,J=5.9 Hz), 6.90(1H,d,J=8.3 Hz), 7.29(1H,dd,J=8.3, 2.4 Hz), 7.46 (2H,d,J=7.8 Hz), 7.58(2H,d,J=7.8 Hz),8.07(1H,d,J=2.4 Hz), 8.34(1H,t,J=5.9 Hz).

Specific rotation [α]_(D) ²⁵+24°(C 0.8, MeOH);

Optical purity 99% e.e.(CHIRAL1 PAC AD 0.0046×0.25 m, eluate;n-hexane:isopropanol:trifluoroacetic acid=80:20:0.2, detectingwave-length; 298 nm, column temperature; 30° C., flow rate; 1.00ml/min).

EXAMPLE 162 (R)-3-(1-valeroyl)-4-benzyloxazolidine-2-one

Potassium t-butoxide (2.47 g, 22.0 mmol) and 50 ml of dehydratedtetrahydrofuran were mixed under an atmosphere of argon and(R)-4-benzyloxazolidine-2-one (3.55 g, 20.0 mmol) dissolved into 30 mlof dehydrated tetrahydrofuran was added dropwise under stirring andcooling with ice. After stirring for 30 minutes under cooling with ice,n-valeroyl chloride (2.60 ml, 21.9 mmol) dissolved in 20 ml ofdehydrated tetrahydrofuran was added dropwise. After completion of thedropwise addition, the mixture was stirred for 1 hour and saturatedaqueous solution of ammonium chloride was added to the reaction mixture,which was extracted with ethyl acetate. The extract was washed withwater, saturated sodium hydrogencarbonate and brine in sequence, thendried over anhydrous sodium sulfate and concentrated. The residue waspurified by silica gel chromatography (eluate n-hexane:ethyl acetate=4:1v/v) to obtain 5.06 g (97%) of the aimed compound as a pale yellow oil.

Mass analysis m/z 261(M⁺).

EXAMPLE 163 Benzyl 5-bromomethyl-2-methoxybenzoate

Benzyl 5-hydroxymethyl-2-methoxybenzoate (Patent Application No. Hei11-162235) (15.5 g, 56.9 mmol) and 300 ml of dehydrated ether were mixedand phosphorus tribromide (2.0 ml, 21.1 mmol) was added dropwise understirring and cooling with ice, which was further stirred for 1 hour. Icewater was added to the reaction mixture and ether layer was separated.The ether layer was washed with water, saturated sodiumhydrogencarbonate and brine in sequence, then dried over anhydroussodium sulfate and concentrated. The crystals obtained wererecrystallized from diisopropyl ether to obtain 12.7 g (66%) of theaimed compound as colorless prisms.

Mass analysis m/z 334, 336(M⁺).

EXAMPLE 164[3(2S),4R]-3-[2-n-propyl-3-[4-methoxy-3-(benzyloxycarbonyl)phenyl]propionyl]-4-benzyloxazolidine-2-one

(R)-3-(1-valeroyl)-4-benzyloxazolidine-2-one (3.56 g, 13.6 mmol) and 70ml of dehydrated tetrahydrofuran were mixed under an atmosphere ofargon, which was cooled to −78° C. Under stirring, 1 mol/l solution ofsodium bis(trimethylsilyl)amide in tetrahydrofuran (15.0 ml, 15.0 mmol)was added dropwise. After completion of the dropwise addition, themixture was stirred for 1 hour at −78° C. and then a solution of benzyl5-bromomethyl-2-methoxybenzoate (5.04 g, 15.0 mmol) in tetrahydrofuran(20 ml) was added dropwise. After completion of the dropwise addition,the mixture was stirred for 3 hours at −78° C., followed by stirring for3 hours at −35 to −40° C. Saturated aqueous solution of ammoniumchloride was added to the reaction mixture, which was extracted withethyl acetate. The extract was washed with water and brine in sequence,then dried over anhydrous sodium sulfate and concentrated. The residuewas purified by silica gel chromatography (eluate n-hexane:ethylacetate=4:1 v/v) to obtain 6.11 g (87%) of the aimed compound as acolorless oil.

Mass analysis m/z 515(M⁺).

EXAMPLE 165[3(2S),4R]-3-[2-ethyl-3-[4-methoxy-3-(benzyloxycarbonyl)phenyl]propionyl]-4-benzyloxazolidine-2-one

Similarly to Example 5, the title compound was obtained as a colorlessoil.

Mass analysis m/z 501(M⁺).

EXAMPLE 166[5(2S,4′R)]-2-methoxy-5-[[-2-(2-oxo-4-benzyloxazolidine-3-yl)carbonyl]pentyl]benzoicacid

[3(2S),4R]-3-[2-n-propyl-3-[4-methoxy-3-(benzyloxycarbonyl)phenyl]propionyl]-4-benzyloxazolidine-2-one(20.9 g, 40.5 mmol), 2.00 g of 10% palladium on activated carbon and 200ml of ethyl acetate were mixed and catalytic hydrogenation was conductedat an initial hydrogen pressure of 294 kPa. After completion of thereaction, catalyst was filtered and washed with ethyl acetate. Thereaction mixture and the washings were combined and concentrated toobtain 17.2 g (100%) of the aimed compound as a colorless oil.

Mass analysis m/z 425(M⁺).

EXAMPLE 167[5(2S,4′R)]-2-methoxy-5-[[2-(2-oxo-4-benzyloxazolidine-3-yl)-carbonyl]butyl]benzoicacid

Similarly to Example 7, the title compound was obtained as a colorlessoil.

Mass analysis m/z 411(M⁺)

EXAMPLE 168[3(2S),4R]-3-[2-n-propyl-3-[4-methoxy-3-[N-[(4-phenoxyphenyl)methyl]carbamoyl]phenyl]propionyl]-4-benzyloxazolidine-2-one

[5(2S,4′R)]-2-methoxy-5-[[2-(2-oxo-4-benzyloxazolidine-3-yl)carbonyl]pentyl]benzoicacid (12.1 g, 28.4 mmol), triethylamine (10.0 ml, 71.7 mmol) and 200 mlof dichloromethane were mixed and ethyl chlorocarbonate (3.05 ml, 31.3mmol) was added dropwise under stirring and cooling with ice, Afterstirring for 20 minutes at 0° C., 4-phenoxybenzylamine hydrochloride(7.37 g, 31.3 mmol) was added little by little. After stirring for 1hour at 0° C., the mixture was stirred for 4 hours at room temperature.The reaction mixture was washed with 0.1 mol/l hydrochloric acid, water,saturated aqueous solution of sodium. hydrogencarbonate and brine insequence, then dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography (eluate n-hexane:ethylacetate=7:3 v/v) to obtain 16.1 g (93%) of the aimed compound as acolorless oily product.

Mass analysis m/z 606(M⁺).

EXAMPLES 169 THROUGH 173

The compounds listed in Table 13 were obtained similarly to Example 168.

TABLE 13

Example R¹ R² R³ Mass analysis (m/z) 169 2-OCH₃ C₂H₅ OCH₃ 622 (M⁺) 1702-OCH₃ n-C₃H₇ OCH₃ 636 (M⁺) 171 3-OCH₃ n-C₃H₇ OCH₃ 636 (M⁺) 172 4-F C₂H₅OCH₃ 610 (M⁺) 173 4-F n-C₃H₇ OCH₃ 624 (M⁺)

EXAMPLE 174(S)-(+)-2-ethyl-3-[4-methoxy-3-[N-[(4-fluorophenoxyphenyl)methyl]carbamoyl]phenyl]propanoicacid

[3(2S),4R]-3-[2-ethyl-3-[4-methoxy-3-[N-[(4-fluorophenoxyphenyl)methyl]carbamoyl]phenyl]propionyl]-4-benzyloxazolidine-2-one(2.02 g, 3.31 mol) was dissolved into 18 ml of mixed solvent oftetrahydrofuran with water (4:1 v/v), which was cooled with ice under anatmosphere of argon. Under stirring, 30% aqueous hydrogen peroxide (1.34ml, 13.2 mmol) was added dropwise over 5 minutes. Following this,lithium hydroxide (222 mg, 5.30 mmol) dissolved in 6 ml of water wasadded dropwise over 5 minutes. The mixture was stirred further for 1hour under cooling with ice. Sodium sulfite (1.37 g, 13.2 mmol)dissolved in 9 ml of water was added dropwise to the reaction mixture,which was stirred for 30 minutes as it was. The reaction mixture waspoured into water, which was extracted with methylene chloride. Theextract was washed with brine, then dried over anhydrous magnesiumsulfate and concentrated. The residue was purified using diisopropylether:acetic acid=40:1 v/v to obtain 1.08 g (yield 73%) of aimedcompound as colorless crystals.

Melting point 95-96° C.;

Mass analysis m/z 451(M⁺);

Elemental analysis C26H26FNO5 (451.49):

Calcd. C, 69.17; H, 5.80; N, 3.10.

Found C, 69.06; H, 5.73; N, 3.17.;

¹H-NMR (400 MHz, CDCl₃) δ0.95(3H,t,J=7.3 Hz), 1.54-1.69(2H,m),2.60-2.65(1H,m), 2.75(1H,dd,J=13.7, 6.4 Hz), 2.96(1H,dd,J=13.7, 7.8 Hz),3.89(3H,s), 4.63(2H,d,J=5.9 Hz), 6.89-7.04(7H,m), 7.28-7.32(3H, m),8.08(1H,d,J=2.4 Hz), 8.24(1H,t,J=5.9 Hz).

Specific rotation [α]_(D) ²⁸+31°(C 0.8, MeCN);

Optical purity 97% e.e.(CHIRAL1 PAC OJ, 0.0046×0.25 m, eluate;n-hexane:isopropanol:trifluoroacetic acid=90:10:0.1, detectingwave-length; 254 nm, column temperature; 40° C., flow rate; 1.00ml/min).

EXAMPLES 175 THROUGH 179

The compounds listed in Table 14 were obtained similarly to Example 174.

TABLE 14

Melting point Charac. Angle of rotation Optical purity Example R¹ R² R³(° C.) formula Elemental analysis (%) ([α]_(D)) (e.e.) 175 2-OCH₃ C₂H₅OCH₃ 121-122 C₂₇H₂₉NO₅ Calcd.; C 69.96, H 6.31, N 3.02 +28° (C 0.57,MeCN) 99% Found; C 69.77, H 6.28, N 3.09 176 2-OCH₃ n-C₃H₇ OCH₃ 98-99C₂₈H₃₁NO₆ Calcd.; C 70.42, H 6.54, N 2.93 +22° (C 0.50, MeCN) 96% Found;C 70.34, H 6.60, N 3.10 177 3-OCH₃ n-C₃H₇ OCH₃ 70-71 C₂₈H₃₁NO₆ Calcd.; C70.42, H 6.54, N 2.93 +22° (C 0.53, MeCN) 98% Found; C 70.52, H 6.54, N3.06 178 H n-C₃H₇ OCH₃ 85-86 C₂₇H₂₉NO₅ Calcd.; C 72.46, H 6.53, N 3.13+23° (C 0.54, MeCN) 97% Found; C 72.42, H 6.54, N 3.19 179 4-F n-C₃H₇OCH₃ 126-127 C₂₇H₂₉FNO₅ Calcd.; C 69.66, H 6.06, N 3.01 +23° (C 0.52,MeCN) 100%  Found; C 69.55, H 6.07, N 3.06

(The determination of optical purity is under the same conditions asExample 174 in Examples 177, 178 and 179, and, in Examples 175 and 176,mixed solvent of n-hexane: isopropanol:trifluoroacetic acid=85:15:0.1was used for eluate and the others are same conditions as in Example174).

EXAMPLES 180 THROUGH 188

The compounds listed in Table 15 were obtained similarly to Example 7.

TABLE 15

Mass analysis Example R¹ R² R⁴ R⁵ (m/z) 180 3-CF₃ C₂H₅ OCH₃ C₂H₅ 437(M⁺) 181 4-OCF₃ C₂H₅ OCH₃ C₂H₅ 453 (M⁺) 182 2-OCH₃ C₂H₅ OCH₃ C₂H₅ 399(M⁺) 183 3-OCH₃ C₂H₅ OCH₃ C₂H₅ 399 (M⁺) 184 4-OCH₃ C₂H₅ OCH₃ C₂H₅ 399(M⁺) 185 4-OPh(4-OC₂H₅) C₂H₅ OCH₃ C₂H₅ 505 (M⁺) 186 4-OPh(4-OnC₃H₇) C₂H₅OCH₃ C₂H₅ 399 (M⁺) 187 4-OPh(4-OC₂H₅) nC₃H₇ OCH₃ C₂H₅ 399 (M⁺) 1884-OPh(4-OnC₃H₇) nC₃H₇ OCH₃ C₂H₅ 399 (M⁺)

EXAMPLES 189 THROUGH 197

The compounds listed in Table 16 were obtained similarly to Example 20.

TABLE 16

Example R¹ R² R⁴ Melting point (° C.) Charac. formula Elemental analysis(%) 189 3-CF₃ C₂H₅ OCH₃ 144-146 C₂₁H₂₂F₃NO₄ Calcd.; C 60.72, H 5.50, N3.37 Found; C 60.87, H 5.31, N 3.43 190 4-OCF₃ C₂H₆ OCH₃ 135-137C₂₁H₂₂F₃NO₆ Calc.; C 59.29, H 5.21, N 3.29 Found; C 58.91, H 5.08, N3.34 191 2-OCH₃ C₂H₅ OCH₃ 120-121 C₂₁H₂₅NO₅.{fraction (1/10)}H₂O Calcd.;C 67.58, H 6.81, N 3.75 Found; C 67.32, H 6.74, N 3.73 192 3-OCH₃ C₂H₅OCH₃ 103-105 C₂₁H₂₅NO₆.½H₂O Calcd.; C 66.30, H 6.89, N 3.68 Found; C66.53, H 6.67, N 3.81 193 4-OCH₃ C₂H₆ OCH₃ 143-144 C₂₁H₂₆NO₆.⅓H₂OCalcd.; C 66.83, H 6.86, N 3.71 Found; C 66.85, H 6.69, N 3.76 1944-OPh(4-OC₂H₅) C₂H₅ OCH₃ 124-125 C₂₈H₃₁NO₆ Calcd.; C 70.86, H 6.77, N2.85 Found; C 70.69, H 6.71, N 2.89 195 4-OPh(4-OnC₃H₇) C₂H₅ OCH₃114-116 C₂₉H₃₃NO₆ Calcd.; C 71.27, H 6.98, N 2.77 Found; C 71.09, H6.92, N 2.87 196 4-OPh(4-OC₂H₅) n-C₃H₇ OCH₃ 123-125 C₂₉H₃₃NO₆ Calcd.; C71.27, H 6.98, N 2.77 Found; C 71.02, H 6.95, N 2.97 197 4-OPh(4-OnC₃H₇)n-C₃H₇ OCH₃ 120-121 C₃₀H₃₅NO₆ Calcd.; C 71.65, H 7.18, N 2.70 Found; C71.35, H 7.17, N 2.85

[Biological Activity]

Test Example 1

Transactivation assay for human peroxisome proliferator-activatedreceptor (PPAR)α

To CHO cells cultured in a Dulbecco-modified Eagle's medium containing10% delipidated fetal calf serum (FCS/DMEM), receptor plasmid thateXpresses fused protein of DNA-binding domain being transcription factorof yeast with ligand-binding domain of human type PPARα (Biochemistry,1993, 32, 5598) its reporter plasmid (STRATAGENE Corp.), and luciferaseplasmid of Renilla (Promega Corp.) as an internal standard werecotransfected with lipofectamine in the serum-free state. Thereafter,testing compound and (8S)-HETE being control compound were added to 10%FCS/DMEM and both luciferase activities were measured after 24 hours,which were corrected with internal standard.

Results are shown in Table 17. From these results, it was shown that theinventive compounds had potent transcriptional activity for humanperoxisome proliferator-activated receptor α.

Test Example 2

Binding assay to human peroxisome proliferator-activated receptor(PPAR)α

A plasmid that eXpresses protein of human PPARα-ligand binding domainattached with histidine tag (His-hPPARα-LBD) was cultured by infectingto Escherichia coli (JM-109) and aimed protein was recovered andpurified.[³H]-5-[(2,4-dioxothiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide(Amasham), testing compound and (8S)-HETE being control compound wereincubated for 45 minutes at room temperature at various concentrationstogether with His-hPPARα-LBD protein in 10 mmol/l Tris hydrochloridebuffer (pH 7.4) containing 50 mmol/l potassium chloride and 10 mmol/ldithiothreitol. After the reaction, amount of[³H]-5-[(2,4-dioxothiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamidewas determined by a liquid scintillation counter.

Results are shown in Table 17. From these results, it was shown that theinventive compounds had potent binding activity to human peroxisomeproliferator-activated receptor α.

TABLE 17 Transcriptional activity Binding activity Example EC₅₀(μmol/l)EC₅₀(μmol/l) 20 0.0115 0.19 22 0.11 0.43 23 0.024 0.74 24 0.18 0.56 300.20 0.84 (8S) HETE 1.30 0.17

Test Example 3

Test on Lipid-lowering Action

After SD strain male rats (Nippon Charles Liver) were bred from 8-(weeksold) with feed (Nippon Clear), test was started from 11-(weeks old).After (fasting) for 2 days, testing compound and Bezafibrate (30 mg/kg),being control compound, suspended into 0.5% solution of arabic gum wereadministered orally once a day for continuous 4 days. For the feedduring administration period, AIN-93M modified fructose-loaded diet(Oriental Yeast) was used. After administration for 4 days, blood wascollected from (trial) vein and the blood levels of triglyceride, totalcholesterol, and free fatty acid were determined by enzymatic method.

The lowering rate of triglyceride in blood, overall cholesterol and freefatty acid was calculated, respectively, by determining the proportionof a figure obtained by subtracting average level of triglyceride inblood (or, average level of (total) cholesterol or level of free fattyacid) of dosage group from average level of triglyceride in blood (or,average level of (total) cholesterol or level of free fatty acid) ofvehicle control group to average level of triglyceride in blood (or,average level of overall cholesterol or level of free fatty acid) ofvehicle control group.

Results are shown in Table 18. As evident from these results, it wasshown that the inventive compounds had excellent blood lipids(cholesterol and neutral lipid)lowering action.

TABLE 18 Lowering rate (%) Dosage Free fatty Total Triglyceride Example(mg/kg) acid cholesterol in blood 20 10 77 25 53 20 30 53 55 56Bezafibrate 30 37 49 64

Test Example 4

Test of transcription activation on human peroxisomeproliferator-activated receptor (PPAR)α

The test of transcription activation on human peroxisomeproliferator-activated receptor (PPAR)α shown in Test example 1 wasperformed to obtain results shown in Table 19.

TABLE 19 Transcriptional activity Example EC₅₀ (μmol/l) 174 0.024 1780.094 179 0.0092

From these results, it was shown that the inventive compounds had potenttranscriptional activity for human peroxisome proliferator-activatedreceptor α.

[Result]

From the results as described above, the inventive substitutedphenylpropanonic acid derivatives are novel compounds group withexcellent binding activity to human PPARα, transcriptional activity, andblood lipids (cholesterol and neutral lipid)-lowering action.

With these inventive compounds, from the fact that they have agonisticactivity on human PPARα, it can be said that they are effectivecompounds as lipid-lowering drugs aforementioned, in particular,lipid-lowering drugs for liver, and suppressing drugs for the progressof arteriosclerosis.

What is claimed is:
 1. A compound represented by formula (1), apharmaceutically salt thereof or a hydrate thereof:

wherein R¹ is a lower alkyl group with 1 to 4 carbon atoms, a loweralkoxy group with 1 to 3 carbon atoms, a trifluoromethyl group, atrifluoromethoxy group, a substituted phenyl group, an unsubstitutedphenyl group, a substituted phenoxy group, an unsubstituted phenoxygroup, a substituted benzyloxy group, or an unsubstituted bezyloxygroup; R² is a lower alkyl group with 1 to 4 carbon atoms, a2,2,2-trifluoroethyl group, a lower alkoxy group with 1 to 3 carbonatoms, a phenoxy group, a lower alkylthio group with 1 to 3 carbonatoms, a phenylthio group, or a benzylthio group, wherein if R² is alower alkyl group with 1 to 4 carbon atoms, or a 2,2,2-trifluoroethylgroup then R³ is a hydrogen atom, or lower alkyl group with 1 to 4carbon atoms; and if R² is a lower alkoxy group with 1 to 3 carbonatoms, a phenoxy group, a lower alkylthio group with 1 to 3 carbonatoms, a phenylthio group, or a benzylthio group then R³ is a hydrogenatom; and R⁴ is a lower alkoxy group with 1 to 3 carbon atoms.
 2. Thecompound, the pharmaceutically acceptable salt thereof, or the hydratethereof according to claim 1, which has the steric configurationrepresented in formula (1a):

wherein R¹ is a lower alkyl group with 1 to 4 carbon atoms, a loweralkoxy group with 1 to 3 carbon atoms, a trifluoromethyl group, atrifluoromethoxy group, a substituted phenyl group, an unsubstitutedphenyl group, a substituted phenoxy group, an unsubstituted phenoxygroup, a substituted benzyloxy group, or an unsubstituted benzyloxygroup; R² is a lower alkyl group with 1 to 4 carbon atoms, a2,2,2-trifluoroethyl group, a lower alkoxy group with 1 to 3 carbonatoms, a lower alkylthio group with 1 to 3 carbon atoms, a phenylthiogroup, or benzylthio group; and R⁴ is a lower alkoxy group with 1 to 3carbon atoms.
 3. The compound, the pharmaceutically acceptable saltthereof, or the hydrate thereof according to claim 1, wherein R¹ is atrifluoromethyl group.
 4. The compound, the pharmaceutically acceptablesalt thereof, or the hydrate thereof according to claim 1, wherein R¹ isa benzyloxy group.
 5. The compound, the pharmaceutically acceptable saltthereof, or the hydrate thereof according to claim 1, wherein R¹ is aphenoxy group.
 6. The compound, the pharmaceutically acceptable saltthereof, or the hydrate thereof according to claim 1, wherein R² is anethyl group.
 7. The compound, the pharmaceutically acceptable saltthereof, or the hydrate thereof according to claim 1, wherein R² is amethoxy group.
 8. The compound, the pharmaceutically acceptable saltthereof, or the hydrate thereof according to claim 1, wherein R² is ann-propyl group.
 9. The compound according to claim 1, which is2-methoxy-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanonicacid, a pharmaceutically acceptable salt, or a hydrate thereof.
 10. Thecompound according to claim 1, which is2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.11. The compound according to claim 1, which is2-n-propyl-3-[4-methoxy-3-[N-[[4-(phenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.12. The compound according to claim 1, which is(+)-2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanonicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.13. The compound, the pharmaceutically acceptable salt thereof, or thehydrate thereof according to claim 1, wherein R¹ is a 3-methoxyphenoxygroup.
 14. The compound, the pharmaceutically acceptable salt thereof,or the hydrate thereof according to claim 1, wherein R¹ is a4-fluorophenoxy group.
 15. The compound, the pharmaceutically acceptablesalt thereof, or the hydrate thereof according to claim 1, wherein R¹ isa 2-methoxyphenoxy group.
 16. The compound according to claim 1, whichis2-ethyl-3-[4-methoxy-3-[N-[[4-(2-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.17. The compound according to claim 1, which is2-n-propyl-3-[4-methoxy-3-[N-[[4-(2-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.18. The compound according to claim 1, which is2-ethyl-3-[4-methoxy-3-[N-[[4-(3-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.19. The compound according to claim 1, which is2-n-propyl-3-[4-methoxy-3-[N-[[4-(3-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.20. The compound according to claim 1, which is2-ethyl-3-[4-methoxy-3-[N-[[4-(4-fluorophenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.21. A compound according to claim 1, which is2-n-propyl-3-[4-methoxy-3-[N-[[4-(4-fluorophenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.22. The compound according to claim 1, which is(S)-2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.23. The compound according to claim 1, which is(S)-2-ethyl-3-[4-methoxy-3-[N-[(4-phenoxyphenyl)methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.24. The compound according to claim 1, which is(S)-2-ethyl-3-[4-methoxy-3-[N-[[4-(2-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.25. The compound according to claim 1, which is(S)-2-ethyl-3-[4-methoxy-3-[N-[[4-(4-fluorophenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.26. The compound according to claim 1, which is(S)-n-propyl-3-[4-methoxy-3-[N-[(4-phenoxyphenyl)methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.27. The compound according to claim 1, which is(S)-n-propyl-3-[4-methoxy-3-[N-[[4-(2-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoic acid, a pharmaceuticallyacceptable salt thereof, or a hydrate thereof.
 28. The compoundaccording to claim 1, which is(S)-n-propyl-3-[4-methoxy-3-[N-[[4-(3-methoxyphenoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.29. The compound according to claim 1, which is(S)-2-n-propyl-3-[4-methoxy-3-[N-[[4-(4-fluorophenoxy)phenyl]methyl]carbamoyl]phenyl]-propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.30. The compound according to claim 1, which is2-Ethyl-3[4-methoxy-3-[N-[[4-(trifluoromethyoxy)phenyl]methyl]carbamoyl]phenyl]propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.31. The compound according to claim 1, which is(S)-(+)-2-Ethyl-3-[4-methoxy-3-[N-[[4-(trifloromethoxy)phenyl]methyl]carbamoyl]phenyl]-propanoicacid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.32. A composition comprising one or more compounds represented byformula (1), pharmaceutically acceptable salts thereof, or hydratesthereof as effective ingredients:

wherein R¹ is a lower alkyl group with 1 to 4 carbon atoms, a loweralkoxy group with 1 to 3 carbon atoms, a trifluoromethyl group, atrifluoromethoxy group, a substituted phenyl group, an unsubstitutedphenyl group, a substituted phenoxy group, an unsubstituted phenoxygroup, a substituted benzyloxy group, or an unsubstituted bezyloxygroup; R² is a lower alkyl group with 1 to 4 carbon atoms, a2,2,2-trifluoroethyl group, a lower alkoxy group with 1 to 3 carbonatoms, a phenoxy group, a lower alkylthio group with 1 to 3 carbonatoms, a phenylthio group, or a benzylthio group, wherein if R² is alower alkyl group with 1 to 4 carbon atoms, or a 2,2,2-trifluoroethylgroup then R³ is a hydrogen atom, or lower alkyl group with 1 to 4carbon atoms; and if R² is a lower alkoxy group with 1 to 3 carbonatoms, a phenoxy group, a lower alkylthio group with 1 to 3 carbonatoms, a phenylthio group, or a benzylthio group then R³ is a hydrogenatom; and R⁴ is a lower alkoxy group with 1 to 3 carbon atoms; and acarrier.
 33. The composition of claim 32 which is a lipid-decreasingdrug.
 34. The composition according to claim 32, which is a humanperoxisome proliferant-activated receptor (PPAR)α agonist.
 35. Thecomposition according to claim 32, which is a therapeutic drug forarteriosclerosis.
 36. A composition comprising one or more compounds,pharmaceutically acceptable salts thereof, or hydrates thereof accordingto claim 2, as effective ingredients; and a carrier.
 37. The compositionaccording to claim 36, which is a lipid-decreasing drug.
 38. Thecomposition according to claim 36, which is a human peroxisomeproliferant-activated receptor (PPAR)α agonist.
 39. The compositionaccording to claim 36, which is a therapeutic drug for arteriosclerosis.40. A process for preparing a compound represented by formula (1a)

comprising reacting compound represented by formula (1e)

with pivaloyl chloride to obtain a compound represented by formula (23)

reacting a compound represented by formula (23) with a compoundrepresented by formula (24)

to obtain a compound represented by formula (25)

separating each diastereomer of the compound of formula (25) byrecrystallization or column chromatography to obtain a compoundrepresented by formula (26)

and hydrolyzing the Xp′ substituent in the compound of formula (26);wherein R¹ is a lower alkyl group with 1 to 4 carbon atoms, a loweralkoxy group with 1 to 3 carbon atoms, a trifluoromethoxy group, asubstituted phenyl group, an unsubstituted phenyl group, a substitutedphenoxy group, an unsubstituted phenoxy group, a substituted benzyloxygroup, or an unsubstituted benzyloxy group; R² is a lower alkyl groupwith 1 to 4 carbon atoms, a 2,2,2-trifluoroethyl group, a lower alkoxygroup with 1 to 3 carbon atoms, a phenoxy group, a lower alkylthio groupwith 1 to 3 carbon atoms, a phenylthio group, or a benzylthio group; R⁴is a lower alkoxy group with 1 to 3 carbon atoms; and Xp′ is anoptically active chiral oxazolodinone.
 41. The process according toclaim 40, wherein the optically active chiral oxazolidinone is selectedfrom the group consisting of 4-benzyl-2-oxazolidinone-3-yl group,4-isopropyl-2-oxazolidinone-3-yl group or 4-phenyl-2-oxazolidinone-3-ylgroup, chiral imidazolidinone, chiral cyclic lactam, and chiral sultam.42. A process for preparing a compound represented by formula (1a)

comprising reacting a compound represented by formula (27)

with a compound represented by formula (30)

to obtain compounds represented by formula (28)

hydrogenolyzing the compound of formula (28) to obtain a compoundrepresented by formula (29)

reacting a compound of formula (29) with a compound represented byformula (7)

to obtain compounds represented by formula (26a)

and hydrolyzing the Xp″ substitutent in the compound of formula (26a)wherein R¹ is a lower alkyl group with 1 to 4 carbon atoms, a loweralkoxy group with 1 to 3 carbon atoms, a trifluoromethyl group, atrifluoromethoxy group, a substituted phenyl group, an unsubstitutedphenyl group, a substituted phenoxy group, an unsubstituted phenoxygroup, a substituted benzyloxy group, or an unsubstituted benzyloxygroup; R² is a lower alkyl group with 1 to 4 carbon atoms, a loweralkoxy group with 1 to 3 carbon atoms, a phenoxy group, a loweralkylthio group with 1 to 3 carbon atoms, a phenylthio group, or abenzylthio group; R⁴ is a lower alkoxy group with 1 to 3 carbon atoms of1 to 3; and Xp″ is a chiral oxazolidinone with an absolute configurationof (R).
 43. The process as claimed in claim 42, wherein Xp″ is selectedfrom the group consisting of (R)-4-benzyl-2-oxazolidinone-3-yl group,(R)-4-isopropyl-2-oxazolidinone-3-yl group or(R)-4-phenyl-2-oxazolidinone-3-yl group, chiral imidazolidinone, chiralcyclic lactam, and chiral sultam.
 44. A method of lowering lipid levelsin the blood of a subject, comprising administering the composition ofclaim 32 to said subject in an amount sufficient to lower the lipidlevels in the blood relative to the lipid levels in the blood prior tosaid administering.
 45. A method of lowering lipid levels in the bloodof a subject, comprising administering the composition of claim 36 tosaid subject in an amount sufficient to lower the lipid levels in theblood relative to the lipid levels in the blood prior to saidadministering.
 46. A method of transactivating a human peroxisomeproliferant-activated receptorα in a cell, comprising administering thecomposition of claim 32 to said cell in an amount sufficient totransactivate the human peroxisome proliferant-activated receptorα inthe cell.
 47. A method of transactivating a human peroxisomeproliferant-activated receptorα in a cell, comprising administering thecomposition of claim 36 to said cell in an amount sufficient totransactivate the human peroxisome proliferant-activated receptorα inthe cell.